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Significant Drug Interactions with Antiretroviral Drugs

2. Introductory Case: Aida . Aida, a 25 year-old HIV woman, comes to your pharmacy with prescriptions for her routine therapy of phenytoin and cotrimoxazole Her recent labs indicate that her repeat TLC is 1000 and she is going to begin treatment with ART Today she is given prescriptions for the f

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Significant Drug Interactions with Antiretroviral Drugs

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    1. Significant Drug Interactions with Antiretroviral Drugs HIV Care and ART: A Course for Pharmacists Unit 8 should take approximately 2 hours and 30 minutes to complete Step 1: Introductory Case Study and Question (Slides 1-3) – 5 minutes Step 2: Unit Introduction and Learning Objectives (Slide 4) – 2 minutes Step 3: Significant Drug Interactions with Antiretroviral Therapy (Slides 5-42) – 60 minutes Step 4: Pharmacokinetic Enhancement (Slides 43-51) – 15 minutes Step 5: Case Studies (Slides 52-71) – 60 minutes Step 6: Key Points, Questions (Slides 72-74) – 5 minutesUnit 8 should take approximately 2 hours and 30 minutes to complete Step 1: Introductory Case Study and Question (Slides 1-3) – 5 minutes Step 2: Unit Introduction and Learning Objectives (Slide 4) – 2 minutes Step 3: Significant Drug Interactions with Antiretroviral Therapy (Slides 5-42) – 60 minutes Step 4: Pharmacokinetic Enhancement (Slides 43-51) – 15 minutes Step 5: Case Studies (Slides 52-71) – 60 minutes Step 6: Key Points, Questions (Slides 72-74) – 5 minutes

    2. 2 Introductory Case: Aida Aida, a 25 year-old HIV+ woman, comes to your pharmacy with prescriptions for her routine therapy of phenytoin and cotrimoxazole Her recent labs indicate that her repeat TLC is 1000 and she is going to begin treatment with ART Today she is given prescriptions for the first line regimen in Ethiopia: nevirapine, lamivudine and stavudine Step 1: Introductory Case Study and Question (Slides 1-3) – 5 minutes Ask a participant to read the case. Ask participants if they have any questions about the information presented. Note: Do not give them further information on the case. Just ask them to consider the information provided to them. Step 1: Introductory Case Study and Question (Slides 1-3) – 5 minutes Ask a participant to read the case. Ask participants if they have any questions about the information presented. Note: Do not give them further information on the case. Just ask them to consider the information provided to them.

    3. 3 Introductory Case: Aida (cont.) Which of the following statements is true about an interaction between these medications? There is no interaction between antiretroviral drugs and phenytoin. They can safely be administered together An interaction exists between phenytoin and nevirapine. The dose of nevirapine must be increased to account for increased metabolism due to phenytoin An interaction exists between phenytoin and cotrimoxazole. They should not be administered together Nevirapine may decrease phenytoin levels and therefore the dose of phenytoin may need to be increased to avoid loss of seizure control Ask participants to silently attempt to answer the question. Explain that the answer to the question will be discussed as the unit progresses. Ask participants to silently attempt to answer the question. Explain that the answer to the question will be discussed as the unit progresses.

    4. 4 Unit Learning Objectives Identify primary drug interaction concepts Describe types and mechanisms of interactions Identify drug interactions commonly encountered with antiretroviral drugs Describe how to manage known interactions Discuss pharmacokinetic enhancement and protease inhibitor combinations Step 2: Unit Introduction and Learning Objectives (Slide 4) – 2 minutes One of the most challenging issues facing providers treating patients with human immunodeficiency virus-1 (HIV) infection is the complex problem of drug interactions associated with highly active antiretroviral therapy (HAART). Guidelines for the initial treatment of HIV infection recommend the use of at least three antiretroviral medications, each of which is associated with significant drug interactions. Further increasing the risk of drug interactions is the concurrent treatment of co-morbid disease states and therapies for prevention and/or treatment of opportunistic infections (OIs). This review focuses on the clinically significant drug interaction associated with the use of HAART. Step 2: Unit Introduction and Learning Objectives (Slide 4) – 2 minutes One of the most challenging issues facing providers treating patients with human immunodeficiency virus-1 (HIV) infection is the complex problem of drug interactions associated with highly active antiretroviral therapy (HAART). Guidelines for the initial treatment of HIV infection recommend the use of at least three antiretroviral medications, each of which is associated with significant drug interactions. Further increasing the risk of drug interactions is the concurrent treatment of co-morbid disease states and therapies for prevention and/or treatment of opportunistic infections (OIs). This review focuses on the clinically significant drug interaction associated with the use of HAART.

    5. 5 Basic Definitions Pharmacokinetic: Refers to what the body does to the drug Associated with the length of time the drug stays in the body “LADME” principle Liberation Absorption Distribution Metabolism Elimination Pharmacodynamic: Refers to what the drug does to the body Can change the pharmacological effect of drugs Examples Bone marrow toxicity caused by ganciclovir or AZT Peripheral neuropathy – ddI, d4T, DDC Pancreatitis – ddI, pentamidine, alcohol Step 3: Significant Drug Interactions with Antiretroviral Therapy (Slides 5-42) – 60 minutes A drug interaction occurs when the pharmacologic action of one drug is altered by the co-administration of another. The mechanism of the interaction may be pharmacokinetic (PK) or pharmacodynamic (PD) in nature. PK interactions: PK principles: Liberation: Release of a drug from its dosage form. Drugs must be in solution for absorption Absorption: movement of a drug from site of administration to blood circulation: occurs mainly in the small intestines because of its large surface area (non-ionized=lipid soluble, which favors absorption) Distribution: drug diffusion or transfer from intra to extra vascular space (tissue) Metabolism: chemical conversion of drugs into compounds which are easier to eliminate (water soluble) Elimination: unchanged drug or metabolite via renal, biliary or pulmonary processes PD interactions: These reactions alter the impact of the drug at target site. An example: “D” drugs have similar side effects and as a result, are used less frequently together due to an increased risk of pancreatitis and neuropathy. Heavy alcohol use with “D” drugs increases the risk of pancreatitis.Step 3: Significant Drug Interactions with Antiretroviral Therapy (Slides 5-42) – 60 minutes A drug interaction occurs when the pharmacologic action of one drug is altered by the co-administration of another. The mechanism of the interaction may be pharmacokinetic (PK) or pharmacodynamic (PD) in nature. PK interactions: PK principles: Liberation: Release of a drug from its dosage form. Drugs must be in solution for absorption Absorption: movement of a drug from site of administration to blood circulation: occurs mainly in the small intestines because of its large surface area (non-ionized=lipid soluble, which favors absorption) Distribution: drug diffusion or transfer from intra to extra vascular space (tissue) Metabolism: chemical conversion of drugs into compounds which are easier to eliminate (water soluble) Elimination: unchanged drug or metabolite via renal, biliary or pulmonary processes PD interactions: These reactions alter the impact of the drug at target site. An example: “D” drugs have similar side effects and as a result, are used less frequently together due to an increased risk of pancreatitis and neuropathy. Heavy alcohol use with “D” drugs increases the risk of pancreatitis.

    6. 6 Mechanisms for Drug Interactions Pharmacokinetic Interactions Altered drug absorption and tissue distribution Chelation, pH, P-gp (efflux proteins or drug transporters) Altered drug metabolism Induction/inhibition, GT,P-gp Reduced renal excretion (P-gp) Altered intracellular activation Impairment of phosphorylation (D4T, ZDV) The outcome of these interactions could be additive/synergistic, antagonistic/opposing or potentiation PK drug interactions may involve: Changes in gastric pH and drug absorption: absorption is sometimes dependent upon acidity of the gut – e.g. ketoconazole requires an acid pH for adequate absorption (drugs and food may change the acidity of the gut and decrease absorption). E.g. fluroquinolones must be taken at least 2 hours prior to antacids or 6 hours after antacids to avoid formation of insoluble complex (chelation). Changes in tissue distribution: protein binding displacement – temporary increase in free drug – also results in greater clearance of drug. Altered drug metabolism mediated by induction or inhibition of CYP450, glucuronyl transferase (GT) or modulation of P glycoprotein (P-gp), an efflux protein. P-gp transports substances from cells to intestinal lumen, urine or bile for destruction. P-gp is present in intestinal epithelial cells, in the liver and kidneys, and at various blood-tissue barriers. Normal P-gp activity protects the brain from excessive accumulation of toxic drugs and metabolites, e.g. selective reduction of CNS adverse effects. P-gp can have undesirable effects, e.g. decreasing the activity of antiretrovirals within the brain. Some drugs may inhibit P-gp resulting in decreased elimination. Ritonavir has been shown to inhibit p-gp mediated transport in renal proximal tubules. Some drugs may induce P-gp (St. John’s Wort) resulting in increased elimination PIs ritonavir, nelfinavir, and amprenavir may strongly induce P-gp expression. Fluctuation in intracellular drug concentrations of active drug (D4T, ZDV) is due to impairment of phosphorylation, which is needed to change the drug to its active state. D4T and ZDV should NEVER be used together. They are antagonistic (PK). Changes in renal elimination may result in increased drug concentrations in the blood.PK drug interactions may involve: Changes in gastric pH and drug absorption: absorption is sometimes dependent upon acidity of the gut – e.g. ketoconazole requires an acid pH for adequate absorption (drugs and food may change the acidity of the gut and decrease absorption). E.g. fluroquinolones must be taken at least 2 hours prior to antacids or 6 hours after antacids to avoid formation of insoluble complex (chelation). Changes in tissue distribution: protein binding displacement – temporary increase in free drug – also results in greater clearance of drug. Altered drug metabolism mediated by induction or inhibition of CYP450, glucuronyl transferase (GT) or modulation of P glycoprotein (P-gp), an efflux protein. P-gp transports substances from cells to intestinal lumen, urine or bile for destruction. P-gp is present in intestinal epithelial cells, in the liver and kidneys, and at various blood-tissue barriers. Normal P-gp activity protects the brain from excessive accumulation of toxic drugs and metabolites, e.g. selective reduction of CNS adverse effects. P-gp can have undesirable effects, e.g. decreasing the activity of antiretrovirals within the brain. Some drugs may inhibit P-gp resulting in decreased elimination. Ritonavir has been shown to inhibit p-gp mediated transport in renal proximal tubules. Some drugs may induce P-gp (St. John’s Wort) resulting in increased elimination PIs ritonavir, nelfinavir, and amprenavir may strongly induce P-gp expression. Fluctuation in intracellular drug concentrations of active drug (D4T, ZDV) is due to impairment of phosphorylation, which is needed to change the drug to its active state. D4T and ZDV should NEVER be used together. They are antagonistic (PK). Changes in renal elimination may result in increased drug concentrations in the blood.

    7. 7 Mechanisms for Drug Interactions (2) Pharmacodynamic interactions Additive or synergistic interactions Antagonistic or opposing interactions PD drug interactions: result in additive effects or synergistic interactions An example of additive effects: bone marrow toxicity caused by ganciclovir and AZT An example of antagonistic effects: indinavir and saquinavir are antagonistic in vitro at higher doses. Piscitelli NEJM 2001PD drug interactions: result in additive effects or synergistic interactions An example of additive effects: bone marrow toxicity caused by ganciclovir and AZT An example of antagonistic effects: indinavir and saquinavir are antagonistic in vitro at higher doses. Piscitelli NEJM 2001

    8. 8 First Pass Effect Recognize that metabolism can occur in the intestines, liver or blood Route of orally administered drugs: Absorbed in the gastrointestinal tract Then pass through the portal venous system to the liver where they are exposed to first pass effect, which may limit systemic circulation Once in the systemic circulation, drugs interact with receptors in target tissues Absorption of drugs from the GI tract depends on the drug's ability to pass across intestinal cell membranes, withstand the highly acidic environment of the stomach, and resist destruction in the liver (first-pass effect). In most cases drugs pass through cell membranes of intestines by simple diffusion, from an area of high concentration (inside the lumen of the intestines) to an area of lower concentration (bloodstream). Active transport across the GI mucosa, very much like a shuttle system, is another way some substances are absorbed. Other factors that may affect absorption of drugs include food and other medications that may inactivate the drug. Extensively metabolized drugs result in minimal delivery to systemic circulation. Metabolism can occur in intestine, blood, or liver. Extensive first pass metabolism of PIs through gut wall and liver may account for poor and variable bioavailability of this class. Refer participants to Handout 8.1, “ARV Effect on CYP450,” as necessary. Absorption of drugs from the GI tract depends on the drug's ability to pass across intestinal cell membranes, withstand the highly acidic environment of the stomach, and resist destruction in the liver (first-pass effect). In most cases drugs pass through cell membranes of intestines by simple diffusion, from an area of high concentration (inside the lumen of the intestines) to an area of lower concentration (bloodstream). Active transport across the GI mucosa, very much like a shuttle system, is another way some substances are absorbed. Other factors that may affect absorption of drugs include food and other medications that may inactivate the drug. Extensively metabolized drugs result in minimal delivery to systemic circulation. Metabolism can occur in intestine, blood, or liver. Extensive first pass metabolism of PIs through gut wall and liver may account for poor and variable bioavailability of this class. Refer participants to Handout 8.1, “ARV Effect on CYP450,” as necessary.

    9. 9 Drug Metabolism and Elimination The goal of metabolism is to change the active form of drugs Making them more water soluble and more readily excreted by kidney or other organs Drug metabolism occurs via two types of reactions: Phase I Phase II Phase I reactions involve oxidation, hydrolysis, and reduction, and take place primarily in the liver through CYP450 (the left side of the diagram) Changing the molecular structure of drugs increases water solubility, which speeds up the excretion of the drug through the kidneys. Oxidative and reduction processes make a molecule's charge more positive or negative than the original drug. Regardless of the positivity or negativity, a charged molecule is dissolvable in water (blood serum is primarily water). Oxidative metabolism may result in formation of an active metabolite or inactive compound, acetates, or sulfates. Phase II reactions involve conjugation (adding another compound) to form glucuronides (the right side of the diagram) Elimination: Fecal excretion is seen with drugs that are not absorbed from the intestines or have been secreted in the bile. Three processes by which drugs are eliminated through the urine: pressure filtration, active tubular secretion or passive diffusion Excretion also occurs through the lungs, perspiration, or breast milk. Phase I reactions involve oxidation, hydrolysis, and reduction, and take place primarily in the liver through CYP450 (the left side of the diagram) Changing the molecular structure of drugs increases water solubility, which speeds up the excretion of the drug through the kidneys. Oxidative and reduction processes make a molecule's charge more positive or negative than the original drug. Regardless of the positivity or negativity, a charged molecule is dissolvable in water (blood serum is primarily water). Oxidative metabolism may result in formation of an active metabolite or inactive compound, acetates, or sulfates. Phase II reactions involve conjugation (adding another compound) to form glucuronides (the right side of the diagram) Elimination: Fecal excretion is seen with drugs that are not absorbed from the intestines or have been secreted in the bile. Three processes by which drugs are eliminated through the urine: pressure filtration, active tubular secretion or passive diffusion Excretion also occurs through the lungs, perspiration, or breast milk.

    10. 10 Cytochrome P450 (CYP450) >30 isoenzymes identified in humans Present in liver, small intestines, lungs, and brain Primary function is to alter toxins (drugs) to speed excretion Nomenclature: Family<subfamily<individual gene (called isoenzyme) Enzyme 3A4 (3 =family, A= subfamily, 4= isoenzyme) Isoenzymes:1A2, 2C9/19, 2D6, 3A4 are primarily responsible for drug metabolism Also metabolize steroid hormones, vitamins, toxins, prostaglandins, fatty acids Knowledge of substrates, inhibitors and inducers helps predict drug interactions Cytochrome P450 (CYP450) is a family of enzymes that accounts for the majority of oxidative metabolism conversion of endogenous substance and drugs. Approximately 50% of all drugs are substrates of CYP3A4, including HIV protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). CYP3A4 resides in the liver and enterocytes of the gastrointestinal tract; therefore partial metabolism begins in the intestine. In humans, cytochrome enzymes are found in many tissues: CYP1A1 Lung, CYP1A2, CYP2C9, CYP2C19 Liver CYP2D6 Liver and Brain CYP3A4 Liver and Small Intestines The primary function of the CYP450 system is to alter toxins (drugs) to speed excretion of foreign bodies. Cytochrome P450 (CYP450) is a family of enzymes that accounts for the majority of oxidative metabolism conversion of endogenous substance and drugs. Approximately 50% of all drugs are substrates of CYP3A4, including HIV protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). CYP3A4 resides in the liver and enterocytes of the gastrointestinal tract; therefore partial metabolism begins in the intestine. In humans, cytochrome enzymes are found in many tissues: CYP1A1 Lung, CYP1A2, CYP2C9, CYP2C19 Liver CYP2D6 Liver and Brain CYP3A4 Liver and Small Intestines The primary function of the CYP450 system is to alter toxins (drugs) to speed excretion of foreign bodies.

    11. 11 Cytochrome P450 Enzymes There is variability in the outcomes of drug interactions involving CYP450. Outcomes are affected by patient factors as well as drug factors. Patient Factors: Genetic polymorphisms are associated with certain ethnic groups. Diseases: Liver disease (decreased enzyme activity, may affect 1st pass effect= increased bioavailability), cardiac failure results in decreased blood flow to the liver Diet/nutrition: grapefruit juice inhibits isoenzyme 3A4 in the intestinal wall, charbroiled meats (due to hydrocarbons) and brussels sprouts can induce isoenzyme 1A2 Smoking: induces CYP 1A1, 1A2, 2E1 Alcohol: chronic drinking induces 2E1 Drug Factors: Dose: Fluconazole at doses over 200-400 mg daily becomes a potent inhibitor of 3A4. Duration: inhibition of CYP450 has a quick onset and a quick offset, whereas induction effects have a long onset and offset Route: the intravenous or intramuscular routes bypass the oral 1st pass effect There is variability in the outcomes of drug interactions involving CYP450. Outcomes are affected by patient factors as well as drug factors. Patient Factors: Genetic polymorphisms are associated with certain ethnic groups. Diseases: Liver disease (decreased enzyme activity, may affect 1st pass effect= increased bioavailability), cardiac failure results in decreased blood flow to the liver Diet/nutrition: grapefruit juice inhibits isoenzyme 3A4 in the intestinal wall, charbroiled meats (due to hydrocarbons) and brussels sprouts can induce isoenzyme 1A2 Smoking: induces CYP 1A1, 1A2, 2E1 Alcohol: chronic drinking induces 2E1 Drug Factors: Dose: Fluconazole at doses over 200-400 mg daily becomes a potent inhibitor of 3A4. Duration: inhibition of CYP450 has a quick onset and a quick offset, whereas induction effects have a long onset and offset Route: the intravenous or intramuscular routes bypass the oral 1st pass effect

    12. 12 P450 Drug Interactions Substrate Medication depends on enzymatic pathway(s) for metabolism Object drug which is affected by inducer or inhibitor Inducer Speeds up metabolism Decreases substrate level (lack of efficacy is concern) Gradual onset/offset Inhibitor Slows metabolism Increases substrate level (toxicity is concern) Quick onset/offset Drugs metabolized by P450 enzymes can have an effect by way of three processes: by metabolism as a substrate, by inhibition or induction of enzymes, or a combination of these three: Substrate: A drug that is metabolized by one or more of the P450 enzymes is said to be a substrate of that enzyme, it is the object drug affected by inducer or inhibitor. Inducer: Increases the amount of P450 enzyme by binding directly to promoter elements in the DNA region that regulates expression of the gene. Induction persists for several days, even after the inducing drug is gone (It takes time to take effect and time to resolve) Inhibitor: This process is almost always competitive and reversible Inhibition of enzymes slows the metabolism of the substrate drug, increasing the level of the drug in the blood. This may result in increased risk of toxicity. The onset of these interactions is quick. Some P450 inhibitors are strong inhibitors, and others are poor. Protease Inhibitors: RTV >>IND>NFV>APV> SQV Knowledge of substrates, inhibitors and inducers helps predict drug interactions. This is important as PIs are metabolized 80-95% by the CYP450 isoenzymes in liver and small intestines. Example: The 20 fold increase in plasma concentration of SQV caused by RTV is probably produced by inhibition of CYP3A4 at both sites. Drugs metabolized by P450 enzymes can have an effect by way of three processes: by metabolism as a substrate, by inhibition or induction of enzymes, or a combination of these three: Substrate: A drug that is metabolized by one or more of the P450 enzymes is said to be a substrate of that enzyme, it is the object drug affected by inducer or inhibitor. Inducer: Increases the amount of P450 enzyme by binding directly to promoter elements in the DNA region that regulates expression of the gene. Induction persists for several days, even after the inducing drug is gone (It takes time to take effect and time to resolve) Inhibitor: This process is almost always competitive and reversible Inhibition of enzymes slows the metabolism of the substrate drug, increasing the level of the drug in the blood. This may result in increased risk of toxicity. The onset of these interactions is quick. Some P450 inhibitors are strong inhibitors, and others are poor. Protease Inhibitors: RTV >>IND>NFV>APV> SQV Knowledge of substrates, inhibitors and inducers helps predict drug interactions. This is important as PIs are metabolized 80-95% by the CYP450 isoenzymes in liver and small intestines. Example: The 20 fold increase in plasma concentration of SQV caused by RTV is probably produced by inhibition of CYP3A4 at both sites.

    13. 13 Pharmacologic action of drug is altered by coadministration of second drug CYP P450 Drug-Drug Interactions Drug-drug interactions can result in a therapeutically desired effect, a negative drug-interaction, a new side effect of a drug, or no consequence at all. The pharmacologic action of one drug is altered by co-administration of second drug. Co administration of the interacting drug may increase the known effect, resulting in increased therapeutic effect or increased toxicity. Co-administration of ritonavir and saquinavir results in a significant increase in saquinavir levels, providing a beneficial interaction and a desired therapeutic effect. Alternatively, lovastatin and simvastatin undergo extensive first-pass metabolism by CYP3A4 and inhibitors of 3A4 (ritonavir) increase the risk of myopathy, in some cases leading to rhabdomyolysis and acute renal failure. The patient should be alert for evidence of myopathy (muscle pain or weakness) and dark urine. Co administration of the interacting drug also may result in a new effect not previously observed with either drug alone. An example: ritonavir is an inhibitor of CYP2D6 and 3A4 and the antidepressant amitriptyline is a substrate of both enzymes. Ritonavir can increase the levels of amitriptyline resulting in elevated concentrations (causing dry mouth, urinary retention, blurred vision, constipation, tachycardia and postural hypotension) and possibly a new side effect: cardiac arrhythmia (due to prolonged QT interval). If used together, amitriptyline should be started at the lowest possible dose and closely monitored. Co administration of the interacting drug may decrease the known effect, resulting in a decreased therapeutic effect of the target drug. For example, rifampin induces the metabolism of PIs, thereby reducing their concentrations and the antiretroviral effect of these drugs. Rifampin gradually reduces the response to oral anticoagulants, the effect may occur as early as a few days to a week with rifampicin and the offset usually takes 2-3 weeks. Consider the increased risk of impaired anticoagulant control and the increased need for monitoring and counseling for signs or symptoms of lack of anticoagulation control.Drug-drug interactions can result in a therapeutically desired effect, a negative drug-interaction, a new side effect of a drug, or no consequence at all. The pharmacologic action of one drug is altered by co-administration of second drug. Co administration of the interacting drug may increase the known effect, resulting in increased therapeutic effect or increased toxicity. Co-administration of ritonavir and saquinavir results in a significant increase in saquinavir levels, providing a beneficial interaction and a desired therapeutic effect. Alternatively, lovastatin and simvastatin undergo extensive first-pass metabolism by CYP3A4 and inhibitors of 3A4 (ritonavir) increase the risk of myopathy, in some cases leading to rhabdomyolysis and acute renal failure. The patient should be alert for evidence of myopathy (muscle pain or weakness) and dark urine. Co administration of the interacting drug also may result in a new effect not previously observed with either drug alone. An example: ritonavir is an inhibitor of CYP2D6 and 3A4 and the antidepressant amitriptyline is a substrate of both enzymes. Ritonavir can increase the levels of amitriptyline resulting in elevated concentrations (causing dry mouth, urinary retention, blurred vision, constipation, tachycardia and postural hypotension) and possibly a new side effect: cardiac arrhythmia (due to prolonged QT interval). If used together, amitriptyline should be started at the lowest possible dose and closely monitored. Co administration of the interacting drug may decrease the known effect, resulting in a decreased therapeutic effect of the target drug. For example, rifampin induces the metabolism of PIs, thereby reducing their concentrations and the antiretroviral effect of these drugs. Rifampin gradually reduces the response to oral anticoagulants, the effect may occur as early as a few days to a week with rifampicin and the offset usually takes 2-3 weeks. Consider the increased risk of impaired anticoagulant control and the increased need for monitoring and counseling for signs or symptoms of lack of anticoagulation control.

    14. 14 Cytochrome P450 Caveats A potent enzyme inhibitor is likely to inhibit the metabolism of ANY drug that is metabolized by that enzyme Some substrates for a particular enzyme are also inhibitors or inducers of that same enzyme Some inhibitors affect more than one enzyme Magnitude of inhibition may depend upon the dose An inhibitor may produce inhibition of an isozyme at one dose, but require a larger dose to inhibit another isozyme Most, but not all, CYP450 inhibitors are eliminated by the liver Enantiomers may be metabolized by different enzymes Some ARVs have mixed effect: EFV, LPV/RTV, RTV A few points to consider when thinking about CYP450 interactions: Some substrates for a particular enzyme are also inhibitors or inducers of that same enzyme due to competitive inhibition of enzyme activity (i.e.. Ritonavir is a substrate and inhibitor of 3A4). Some inhibitors affect more than one enzyme (for example EFV inhibits 2C9, 2C19, induces 3A4, and is a substrate for 2D6 and 3A4) Magnitude of inhibition may depend upon the dose (i.e. Cimetidine 1200 mg/day is a more potent inhibitor of drug metabolism than 400 mg/day). An inhibitor may produce inhibition of an isozyme at one dose, but require a larger dose to inhibit another isozyme (Fluconazole inhibits 2C9 at low doses such as 100 mg daily, but at large doses 200-400 mg daily, it inhibits 3A4). Most CYP450 inhibitors are eliminated by the liver, but some are not (for example, fluconazole is eliminated by the kidneys). Enantiomers (L/D) may be metabolized by different enzymes (For example, the relatively weak anticoagulant R-warfarin is metabolized primarily by CYP1A2, while the more potent S-warfarin is metabolized by CYP2C9. Thus inhibitors of CYP1A2 tend to produce only small increases in the hypoprothrombinemic response to warfarin, while CYP2C9 inhibitors (EFV, metronidazole) can sometimes produce large increases in warfarin response. Some ARVs have mixed effect (induction and inhibition): EFV,Lop/r, RTV. A few points to consider when thinking about CYP450 interactions: Some substrates for a particular enzyme are also inhibitors or inducers of that same enzyme due to competitive inhibition of enzyme activity (i.e.. Ritonavir is a substrate and inhibitor of 3A4). Some inhibitors affect more than one enzyme (for example EFV inhibits 2C9, 2C19, induces 3A4, and is a substrate for 2D6 and 3A4) Magnitude of inhibition may depend upon the dose (i.e. Cimetidine 1200 mg/day is a more potent inhibitor of drug metabolism than 400 mg/day). An inhibitor may produce inhibition of an isozyme at one dose, but require a larger dose to inhibit another isozyme (Fluconazole inhibits 2C9 at low doses such as 100 mg daily, but at large doses 200-400 mg daily, it inhibits 3A4). Most CYP450 inhibitors are eliminated by the liver, but some are not (for example, fluconazole is eliminated by the kidneys). Enantiomers (L/D) may be metabolized by different enzymes (For example, the relatively weak anticoagulant R-warfarin is metabolized primarily by CYP1A2, while the more potent S-warfarin is metabolized by CYP2C9. Thus inhibitors of CYP1A2 tend to produce only small increases in the hypoprothrombinemic response to warfarin, while CYP2C9 inhibitors (EFV, metronidazole) can sometimes produce large increases in warfarin response. Some ARVs have mixed effect (induction and inhibition): EFV,Lop/r, RTV.

    15. 15 Pharmacist Beware A drug interaction can occur whenever a: New medication is started Medication is discontinued Dose is changed Drug is changed Remember: Inducing interactions Gradual onset/offset Inhibiting interactions Quick onset/offset For example: let’s say that a patient is on a drug that is a substrate for an enzyme and also on a medication that induces that enzyme. If the inducing drug is discontinued, the level of the substrate drug may now be increased and could lead to toxicity.For example: let’s say that a patient is on a drug that is a substrate for an enzyme and also on a medication that induces that enzyme. If the inducing drug is discontinued, the level of the substrate drug may now be increased and could lead to toxicity.

    16. 16 Red Flags for Potential Interactions PIs or NNRTIs and Statins Ergot alkaloids Azole antifungals Antihistamines Anticonvulsants Anti-tuberculars (rifamycins) Warfarin Benzodiazepines Alternative medicine Cardiac medicine Amiodarone, quinidine Oral contraceptives Containing estradiol Macrolide antibiotics Methadone Pharmacists play a critical role in detecting drug interactions, before they happen. Pharmacists need to ask patients what other medications they are currently taking whenever dispensing a new medication to avoid potential interactions. Also, be aware that when a medication dose is changed or discontinued, that can have an effect on any other drug that it interacts with. The facilitator can ask the audience if anyone knows what red flags for potential interactions means clinically. Answer: Drugs or drug classes that are Red Flags for drug interactions are those that are known to cause significant interactions with PIs and NNRTIs and should always be approached with caution, or in some cases avoided completely with ARV medications.Pharmacists play a critical role in detecting drug interactions, before they happen. Pharmacists need to ask patients what other medications they are currently taking whenever dispensing a new medication to avoid potential interactions. Also, be aware that when a medication dose is changed or discontinued, that can have an effect on any other drug that it interacts with. The facilitator can ask the audience if anyone knows what red flags for potential interactions means clinically. Answer: Drugs or drug classes that are Red Flags for drug interactions are those that are known to cause significant interactions with PIs and NNRTIs and should always be approached with caution, or in some cases avoided completely with ARV medications.

    17. 17 CYP 3A4: Substrates Alpra-, tria-, mida- zolam Calcium channel blockers Carbamazepine Corticosteroids Digoxin Cyclosporine Methadone The isoenzyme 3A4 is responsible for the metabolism of the PI and NNRTI class of ARVs. It is the isoenzyme that is responsible for the majority of drug interactions that are encountered by a patient on a PI or NNRTI The following two slides are lists of the common substrates of CYP 3A4. Substrates of 3A4 may be affected by either inhibition by PIs (which may result in toxic levels) or by induction from NNRTIs, which may result in loss of therapeutic efficacy. Some interactions are known and predictable, whereas others are based on theoretical considerations due to the known metabolism of the drugs. This list may be used later as a reference for the cases we will review. The isoenzyme 3A4 is responsible for the metabolism of the PI and NNRTI class of ARVs. It is the isoenzyme that is responsible for the majority of drug interactions that are encountered by a patient on potent ARVs, (which include either a PI or NNRTI) The isoenzyme 3A4 is responsible for the metabolism of the PI and NNRTI class of ARVs. It is the isoenzyme that is responsible for the majority of drug interactions that are encountered by a patient on a PI or NNRTI The following two slides are lists of the common substrates of CYP 3A4. Substrates of 3A4 may be affected by either inhibition by PIs (which may result in toxic levels) or by induction from NNRTIs, which may result in loss of therapeutic efficacy. Some interactions are known and predictable, whereas others are based on theoretical considerations due to the known metabolism of the drugs. This list may be used later as a reference for the cases we will review. The isoenzyme 3A4 is responsible for the metabolism of the PI and NNRTI class of ARVs. It is the isoenzyme that is responsible for the majority of drug interactions that are encountered by a patient on potent ARVs, (which include either a PI or NNRTI)

    18. 18 CYP 3A4: Substrates (2) Protease inhibitors Statins Amitriptyline Quinidine Terfenadine Pimozide Many, many more These are additional drugs that are substrates of CYP3A4. Other common substrates of 3A4 include nefazodone, astemizole, cisapride, sildenafil.These are additional drugs that are substrates of CYP3A4. Other common substrates of 3A4 include nefazodone, astemizole, cisapride, sildenafil.

    19. 19 CYP 3A4: Inhibitors Erythro-, > clarithromycin Delavirdine Efavirenz Fluoxetine Fluvoxamine Grapefruit juice Keto-, itra- > fluconazole PIs: ritonavir >>> amprenavir, atazanavir, indinavir, nelfinavir > saquinavir Potent inhibitors that should be red flags for potential drug interactions: macrolide antibiotics including erythromycin, clarithromycin, antidepressants including fluoxetine and fluvoxamine, azole antifungals such as ketoconazole and itraconazole, fluconazole at higher doses >200 mg/day. Of the PIs, ritonavir has the greatest inhibitory effect on 3A4, followed by amprenavir, atazanavir, indinavir, nelfinavir and saquinavir. Efavirenz is a moderate 3A4 inhibitor. Reference note: Grapefruit juice: mainly 3A4 inhibition, some 1A2 and 2D6 inhibition as well. It takes 2 or 3 8 oz glasses of grapefruit juice per day to cause inhibition. This is due to bioflavonoids - naringin (which gives grapefruit its bitter flavor) not present in other citrus fruits. It is metabolized to naringenin which is a potent CYP3A4 inhibitor.Potent inhibitors that should be red flags for potential drug interactions: macrolide antibiotics including erythromycin, clarithromycin, antidepressants including fluoxetine and fluvoxamine, azole antifungals such as ketoconazole and itraconazole, fluconazole at higher doses >200 mg/day. Of the PIs, ritonavir has the greatest inhibitory effect on 3A4, followed by amprenavir, atazanavir, indinavir, nelfinavir and saquinavir. Efavirenz is a moderate 3A4 inhibitor. Reference note: Grapefruit juice: mainly 3A4 inhibition, some 1A2 and 2D6 inhibition as well. It takes 2 or 3 8 oz glasses of grapefruit juice per day to cause inhibition. This is due to bioflavonoids - naringin (which gives grapefruit its bitter flavor) not present in other citrus fruits. It is metabolized to naringenin which is a potent CYP3A4 inhibitor.

    20. 20 CYP 3A4: Inducers Inducers Carbamazepine, phenytoin, phenobarbital Rifampin, rifabutin, St. John’s wort, garlic Efavirenz, nevirapine Potent inducers of 3A4 that should be red flags for potential drug interactions include anticonvulsants, rifamycin antibiotics, and the NNRTIs NVP and EFV (nelfinavir has been reported to decrease serum concentrations of methadone and ethinyl estradiol, suggesting that it might be an inducer of 3A4 in some situations. In general, it is not viewed as an inducer). Co administered RTV may decrease serum concentrations of phenytoin due to effects associated with the CYP450 system. The clinical significance of this potential interaction is currently undetermined. The effect may be due to induction of phenytoin metabolism. It may be necessary to monitor phenytoin serum concentrations. Also, observe patients for signs of decreased phenytoin efficacy, including seizure activity. Severity is moderate and onset is delayed. Phenytoin may affect levels of PIs or NNRTIs. This combination should be avoided, if possible. The effects of anticonvulsants carbamazepine and phenobarbital are unknown. The recommendation is that anticonvulsant levels should be monitored, and used with extreme caution when used with ART.Potent inducers of 3A4 that should be red flags for potential drug interactions include anticonvulsants, rifamycin antibiotics, and the NNRTIs NVP and EFV (nelfinavir has been reported to decrease serum concentrations of methadone and ethinyl estradiol, suggesting that it might be an inducer of 3A4 in some situations. In general, it is not viewed as an inducer). Co administered RTV may decrease serum concentrations of phenytoin due to effects associated with the CYP450 system. The clinical significance of this potential interaction is currently undetermined. The effect may be due to induction of phenytoin metabolism. It may be necessary to monitor phenytoin serum concentrations. Also, observe patients for signs of decreased phenytoin efficacy, including seizure activity. Severity is moderate and onset is delayed. Phenytoin may affect levels of PIs or NNRTIs. This combination should be avoided, if possible. The effects of anticonvulsants carbamazepine and phenobarbital are unknown. The recommendation is that anticonvulsant levels should be monitored, and used with extreme caution when used with ART.

    21. 21 Introductory Case: Aida (cont.) There is no interaction between ART and phenytoin. They can safely be administered together FALSE The interaction between phenytoin and nevirapine is unknown. Both drugs are cytochrome P450 3A4 inducers and therefore an interaction can be anticipated

    22. 22 An interaction exists between phenytoin and nevirapine. The dose of nevirapine must be increased to account for increased metabolism due to phenytoin FALSE Phenytoin may decrease the levels of nevirapine, however, the interaction is unknown Levels of nevirapine should not be increased empirically If there are no other options for anti-seizure medications for this patient, and this combination must be used, the patient should be monitored for loss of virologic control Introductory Case: Aida (cont.)

    23. 23 CYP 2C9/19 Substrates Diazepam NSAIDs Phenobarbital Phenytoin Tolbutamide S-warfarin Sertaline Inhibitors Ritonavir Delavirdine Efavirenz Cimetidine Fluoxetine Fluvoxamine Omeprazole TMP/SMX EFV and Ritonavir are inhibitors of 2C9 which may increase the level of certain substrates, for example: phenytoin. It is not easy to predict the outcome of the interaction between anticonvulsants and NNRTIs as the effect can be mixed. Anticonvulsants are also inducers of CYP2C9 and 2C19.EFV and Ritonavir are inhibitors of 2C9 which may increase the level of certain substrates, for example: phenytoin. It is not easy to predict the outcome of the interaction between anticonvulsants and NNRTIs as the effect can be mixed. Anticonvulsants are also inducers of CYP2C9 and 2C19.

    24. 24 Part 1: An interaction exists between phenytoin and Cotrimoxazole TRUE Part 2: They should not be administered together FALSE Cotrimoxazole is an inhibitor of CYP 2C9 and phenytoin is a substrate of the same enzyme. The levels of phenytoin may be increased when Cotrimoxazole is started (after a few weeks) This patient has been taking both medications together and is stable on therapy. She can continue to receive these medications together Introductory Case: Aida (cont.)

    25. 25 CYP 2D6: Substrates Amphetamines Codeine-to-morphine Encainide, flecainide Haloperidol Hydrocodone-to-morphine Metoprolol, propranolol Phenothiazines Risperidone SSRIs TCAs (amitriptyline) Substrates of 2D6 may be affected by CYP2D6 inhibitors including ritonavir. Many antidepressants are metabolized by CYP2D6 and may be affected by PIs. Amitriptyline is a substrate for 2D6. It is the primary path by which it is metabolized. Ask participants, “What is the best way to manage the known drug interactions between antidepressants and ARVs? First, let’s review common inhibitors (next slide).”Substrates of 2D6 may be affected by CYP2D6 inhibitors including ritonavir. Many antidepressants are metabolized by CYP2D6 and may be affected by PIs. Amitriptyline is a substrate for 2D6. It is the primary path by which it is metabolized. Ask participants, “What is the best way to manage the known drug interactions between antidepressants and ARVs? First, let’s review common inhibitors (next slide).”

    26. 26 CYP 2D6: Inhibitors Ritonavir Cimetidine Fluoxetine Haloperidol Paroxetine Quinidine Methadone

    27. 27 PI/ NNRTI/ Antidepressant Drug Interactions When using antidepressants with ARVs, the message is to start low and go slow. Example: Co-administered ritonavir may increase serum concentrations of amitriptyline, resulting in amitriptyline toxicity. Adverse Effect: increased amitriptyline serum concentrations which may lead to (anticholinergic effects, like dry mouth, urinary retention, blurred vision, other effects include: sedation, confusion, cardiac arrhythmias). Monitor amitriptyline levels where possible. Monitor patients for signs and symptoms of tricyclic antidepressant toxicity (anticholinergic effects, sedation, confusion, cardiac arrhythmias). Reduce doses of amitriptyline as required. Start with 50% of the normal starting dose (use 25 mg qhs rather than 50 mg. Maximum 75 mg/day) On the other hand, 3A4 inducers like nevirapine may decrease amitriptyline levels. This is probably not a significant interaction. Increased levels of certain antidepressants can cause “serotonin syndrome” which can present as: mental status changes, agitation, tremor, shivering, sweating, fever, muscle spasm, hypertension seizures. Reducing SSRI dosages by one-half when used with ritonavir has been recommended to minimize adverse effects from a pharmacokinetic interaction.When using antidepressants with ARVs, the message is to start low and go slow. Example: Co-administered ritonavir may increase serum concentrations of amitriptyline, resulting in amitriptyline toxicity. Adverse Effect: increased amitriptyline serum concentrations which may lead to (anticholinergic effects, like dry mouth, urinary retention, blurred vision, other effects include: sedation, confusion, cardiac arrhythmias). Monitor amitriptyline levels where possible. Monitor patients for signs and symptoms of tricyclic antidepressant toxicity (anticholinergic effects, sedation, confusion, cardiac arrhythmias). Reduce doses of amitriptyline as required. Start with 50% of the normal starting dose (use 25 mg qhs rather than 50 mg. Maximum 75 mg/day) On the other hand, 3A4 inducers like nevirapine may decrease amitriptyline levels. This is probably not a significant interaction. Increased levels of certain antidepressants can cause “serotonin syndrome” which can present as: mental status changes, agitation, tremor, shivering, sweating, fever, muscle spasm, hypertension seizures. Reducing SSRI dosages by one-half when used with ritonavir has been recommended to minimize adverse effects from a pharmacokinetic interaction.

    28. 28 ARV Interactions with Pain Medication: Methadone Interactions Primarily metabolized by 3A4 Likelihood for interactions with PIs/NNRTIs is high Numerous studies/case reports Difficult to determine effect due to long half-life of methadone and differential effects on inactive S(+) enantiomer versus active R(-) enantiomer Watch for signs of opiate withdrawal Methadone may increase zidovudine levels – watch for increased nausea/vomiting If methadone is used for pain, this may result in significant interactions with PIs or NNRTIs because it is primarily metabolized by 3A4. This may result in a need for a dose increase of methadone. The methadone dose increase, if needed, may not always parallel the reduction in total methadone exposure. For example, data reported by Clarke et. al suggest that despite a decrease of >50% in methadone AUC seen with the addition of efavirenz, a mean increase in methadone dose of only 22% (in 10 mg increments) was required to counteract symptoms consistent with opiate withdrawal. Methadone inhibits glucuronidation of zidovudine and to a lesser extent renal clearance of zidovudine. Monitor for zidovudine related toxicities, ie, nausea, vomiting, headaches and myelosuppression (affect all cell lines in the bone marrow).If methadone is used for pain, this may result in significant interactions with PIs or NNRTIs because it is primarily metabolized by 3A4. This may result in a need for a dose increase of methadone. The methadone dose increase, if needed, may not always parallel the reduction in total methadone exposure. For example, data reported by Clarke et. al suggest that despite a decrease of >50% in methadone AUC seen with the addition of efavirenz, a mean increase in methadone dose of only 22% (in 10 mg increments) was required to counteract symptoms consistent with opiate withdrawal. Methadone inhibits glucuronidation of zidovudine and to a lesser extent renal clearance of zidovudine. Monitor for zidovudine related toxicities, ie, nausea, vomiting, headaches and myelosuppression (affect all cell lines in the bone marrow).

    29. 29 Metabolic Characteristics of ARVs This is a summary slide of the effects of ARVs on CYP450 for reference. Remember that in general, the NNRTIs are inducers of 3A4 and the PIs are inhibitors of 3A4, to varying degrees. However, some ARV have mixed effects on different enzymes which may make it difficult to predict drug interactions, and may require close clinical monitoring. This is a summary slide of the effects of ARVs on CYP450 for reference. Remember that in general, the NNRTIs are inducers of 3A4 and the PIs are inhibitors of 3A4, to varying degrees. However, some ARV have mixed effects on different enzymes which may make it difficult to predict drug interactions, and may require close clinical monitoring.

    30. 30 PI: Safer Choices Anxiety/insomnia Use Diphenhydramine, Temazepam or Oxazepam MAI prophylaxis/treatment Use Azithromycin Antidepressants Start low and go slow! Amitriptyline: 2D6 and 32A4 substrate Fluoxetine and Fluvoxamine: broad CYP450 inhibition (serotonin syndrome) Sertraline: minimal 3A4 inhibition, may be sig.>150 mg/day There are safer choices for certain classes of medications where known potential interactions exist when co-administered with PIs. For the benzodiazepine class, when given orally, alprazaolam, midazolam and triazolam undergo extensive first pass metabolism by CYP3A4 in the gut wall and liver. These benzodiazepines are contraindicated with all PIs. The primary risk is impairment of motor skills that could result in falls or motor vehicle accidents. Alternatively, temazepam, oxazepam or lorazepam are largely glucuronidated and are unlikely to be affected by CYP3A4 inhibitors. Other benzodiazepines such as diazepam or clonazepam are also at least partially metabolized by CYP3A4 and may also interact with CYP3A4 inhibitors. When using macrolide antibiotics for MAI prophylaxis, unlike clarithromycin and erythromycin, azithromycin does not appear to inhibit 3A4. For example: When using clarithromycin with efavirenz, the levels of clarithromycin are decreased by 39%, efficacy of the antibiotic must be monitored. When using clarithromycin with nevirapine, the NVP levels are increased by 26% and clarithromycin levels are decreased by 30%. When using clarithromycin with ritonavir, clarithromycin levels are increased by 77%. No dose adjustment is recommended unless patients have renal impairment. Clarithromycin can prolong the QT interval at high doses. Avoid this combination if azithromycin is available. When starting an antidepressant in a patient on a ritonavir containing regimen, the lowest possible dose should be used and the patient should be monitored for the development of toxicity (dry mouth, constipation, blurred vision, tachycardia, constipation and postural hypotension). There are safer choices for certain classes of medications where known potential interactions exist when co-administered with PIs. For the benzodiazepine class, when given orally, alprazaolam, midazolam and triazolam undergo extensive first pass metabolism by CYP3A4 in the gut wall and liver. These benzodiazepines are contraindicated with all PIs. The primary risk is impairment of motor skills that could result in falls or motor vehicle accidents. Alternatively, temazepam, oxazepam or lorazepam are largely glucuronidated and are unlikely to be affected by CYP3A4 inhibitors. Other benzodiazepines such as diazepam or clonazepam are also at least partially metabolized by CYP3A4 and may also interact with CYP3A4 inhibitors. When using macrolide antibiotics for MAI prophylaxis, unlike clarithromycin and erythromycin, azithromycin does not appear to inhibit 3A4. For example: When using clarithromycin with efavirenz, the levels of clarithromycin are decreased by 39%, efficacy of the antibiotic must be monitored. When using clarithromycin with nevirapine, the NVP levels are increased by 26% and clarithromycin levels are decreased by 30%. When using clarithromycin with ritonavir, clarithromycin levels are increased by 77%. No dose adjustment is recommended unless patients have renal impairment. Clarithromycin can prolong the QT interval at high doses. Avoid this combination if azithromycin is available. When starting an antidepressant in a patient on a ritonavir containing regimen, the lowest possible dose should be used and the patient should be monitored for the development of toxicity (dry mouth, constipation, blurred vision, tachycardia, constipation and postural hypotension).

    31. 31 PI: Safer Choices (2) Anticonvulsants Use sodium valproate, gabapentin or lamotrigene, if possible. If use with phenytoin, phenobarbitol, or carbamazepine, need to monitor antiseizure activity Migraine therapy Use paracetamol, sumatriptan, or narcotic analgesics Antihistamines Use loratadine or cetirizine or diphenhydramine Rifampicin (only use with adjusted doses of EFZ) Rifabutin, if possible Requires dose reduction with all PIs and dose increase with efavirenz Carbamazepine levels are increased when co-administered with ritonavir. Use with caution and monitor carbamazepine levels, if possible. Carbamazepine greatly decreases IDV and SQV levels and would most likely have the same effect on all other PIs. Phenytoin decreases the levels of LPV and RTV and the levels of phenytoin are decreased as well. It is recommended that these drugs should not be co-administered, if other anticonvulsant possibilities exist. Otherwise the patient must be monitored for virologic failure or anticonvulsant failure. Monitoring anticonvulsant levels is suggested if co-administered. When treating migraines, a safer choice of medication to use with PIs is sumatriptan. It is metabolized hepatically, not by CYP450. Use loratadine or cetriizine for antihistamine therapy. They are safer options than other antihistamines, which may cause cardiac arrythmias at high doses. Rifampicin: maintain EFV dose of 600 mg QHS in patients weighing < 50 kg or consider increasing EFV to 800 mg qhs. Lopinavir /ritonavir should not be co administered with rifampicin. In one small study, higher doses of RTV (an additional 300 mg BID) or a double dose of LPV/RTV offset rifampicin inducing activity of LPV. Of note, 28% of patients discontinued treatment because of increases in LFTs. The safety of this combination is still under evaluation. Further studies are needed. The combination of ritonavir/saquinavir should not be used with rifampicin as it has led to marked elevations in liver enzymes. Doses used were SQV 1000 mg/RTV 100 mg BID + rifampicin 600 mg QD (www.aidsinfo.gov).Carbamazepine levels are increased when co-administered with ritonavir. Use with caution and monitor carbamazepine levels, if possible. Carbamazepine greatly decreases IDV and SQV levels and would most likely have the same effect on all other PIs. Phenytoin decreases the levels of LPV and RTV and the levels of phenytoin are decreased as well. It is recommended that these drugs should not be co-administered, if other anticonvulsant possibilities exist. Otherwise the patient must be monitored for virologic failure or anticonvulsant failure. Monitoring anticonvulsant levels is suggested if co-administered. When treating migraines, a safer choice of medication to use with PIs is sumatriptan. It is metabolized hepatically, not by CYP450. Use loratadine or cetriizine for antihistamine therapy. They are safer options than other antihistamines, which may cause cardiac arrythmias at high doses. Rifampicin: maintain EFV dose of 600 mg QHS in patients weighing < 50 kg or consider increasing EFV to 800 mg qhs. Lopinavir /ritonavir should not be co administered with rifampicin. In one small study, higher doses of RTV (an additional 300 mg BID) or a double dose of LPV/RTV offset rifampicin inducing activity of LPV. Of note, 28% of patients discontinued treatment because of increases in LFTs. The safety of this combination is still under evaluation. Further studies are needed. The combination of ritonavir/saquinavir should not be used with rifampicin as it has led to marked elevations in liver enzymes. Doses used were SQV 1000 mg/RTV 100 mg BID + rifampicin 600 mg QD (www.aidsinfo.gov).

    32. 32 Nevirapine may decrease phenytoin levels and therefore the dose of phenytoin may need to be increased to avoid loss of seizure control TRUE The patient would need to be monitored closely for loss of seizure control and then the dose would need to be adjusted accordingly by the physician The best option would be to gradually switch the patient from phenytoin to another drug for seizure control, one that does not interact with ART. Options may include sodium valproate or gabapentin Introductory Case: Aida (cont.)

    33. 33 Ritonavir: Do NOT Co-administer Antiarrhythmics Amiodarone, quinidine Antihistamines – terfenadine,* astemizole* Ergot derivatives* (ergotamine) Herbal Preparations HMG-CoA Reductase Inhibitors – lovastatin*, simvastatin* Neuroleptic – Pimozide* (Orap) Benzodiazepines – midazolam,* triazolam* GI – cisapride* * These drugs must also never be co-administered with any PIs Although data are limited, any CYP3A4 inhibitor could increase the plasma concentrations of amiodarone or quinidine. Toxicity including cardiac arrhythmia could result. Assume that all CYP3A4 inhibitors interact until proven otherwise. Monitor for altered antiarrythmic response if the CYP3A4 inhibitor is initiated, discontinued or changed in dosage. Monitor for ECG changes indicating antiarrhythmic toxicity. Monitoring of the antiarrhythmic plasma levels is advised. Co-administered with antihistamines, RTV is contraindicated because it may increase serum levels of terfenadine, causing a potential risk of serious or life-threatening cardiac arrhythmias (QT prolongation, torsades, cardiac arrest) (Prod Info Invirase 2003; Norvir 2000). The co-administration of RTV and ergot derivatives is contraindicated due to the potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by nausea, vomiting, peripheral vasospasm and ischemia of the extremities and other tissues. Onset: rapid Herbal preparations can have a negative impact on ART levels. Until more is known about ART use in Ethiopia, the recommendation would be to avoid use. HMG-CoA Reductase = 3-Hydroxy Methyl Glutaric Acid-CoA Reductase Although data are limited, any CYP3A4 inhibitor could increase the plasma concentrations of amiodarone or quinidine. Toxicity including cardiac arrhythmia could result. Assume that all CYP3A4 inhibitors interact until proven otherwise. Monitor for altered antiarrythmic response if the CYP3A4 inhibitor is initiated, discontinued or changed in dosage. Monitor for ECG changes indicating antiarrhythmic toxicity. Monitoring of the antiarrhythmic plasma levels is advised. Co-administered with antihistamines, RTV is contraindicated because it may increase serum levels of terfenadine, causing a potential risk of serious or life-threatening cardiac arrhythmias (QT prolongation, torsades, cardiac arrest) (Prod Info Invirase 2003; Norvir 2000). The co-administration of RTV and ergot derivatives is contraindicated due to the potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by nausea, vomiting, peripheral vasospasm and ischemia of the extremities and other tissues. Onset: rapid Herbal preparations can have a negative impact on ART levels. Until more is known about ART use in Ethiopia, the recommendation would be to avoid use. HMG-CoA Reductase = 3-Hydroxy Methyl Glutaric Acid-CoA Reductase

    34. 34 NNRTIs: Do NOT Co-administer Ergot derivatives (ergotamine) Benzodiazepine: midazolam, triazolam Rifampicin (Nevirapine) – unless there is NO alternative Terfenadine (Efavirenz) Herbal – St. Johns wort Concomitant use of nevirapine and ergot alkaloids such as ergotamine is predicted to result in decreased plasma concentrations of the ergot alkaloid. Caution is advised and dosage adjustments of the ergot alkaloid may be necessary. As stated in the TB unit, NVP is only to be used with rifampicin if there are no other choices available. Terfenadine and Midazolam are CYP3A4 substrates and EFV is its inducer. Midazolam and triazolam should not be combined with EFV; they can be used with NVP. St. Johns Wort is CYP3A4 inducer. Concomitant use of St. John’s wort (Hypericum perforatum) and nevirapine is not recommended as it results in suboptimal antiretroviral concentrations and may be associated with loss of virologic response and development of resistance. Preliminary data suggest that this drug interaction occurs because St. John’s wort is a potent inducer of CYP isoenzymes responsible for metabolism of indinavir. St. John’s wort is an extract of hypericum and contains at least 7 different components that may contribute to its pharmacologic effects, including hypericin, pseudohypericin, and hyperforin. There is evidence that hypericum extracts can induce several different CYP isoenzymes, including CYP3A4 and CYP1A2, and also may induce the p-glycoprotein transport system. Therefore, it has been recommended that concomitant use of St. John’s wort and HIV protease inhibitors or NNRTIs metabolized by CYP isoenzymes be avoided. Concomitant use of nevirapine and ergot alkaloids such as ergotamine is predicted to result in decreased plasma concentrations of the ergot alkaloid. Caution is advised and dosage adjustments of the ergot alkaloid may be necessary. As stated in the TB unit, NVP is only to be used with rifampicin if there are no other choices available. Terfenadine and Midazolam are CYP3A4 substrates and EFV is its inducer. Midazolam and triazolam should not be combined with EFV; they can be used with NVP. St. Johns Wort is CYP3A4 inducer. Concomitant use of St. John’s wort (Hypericum perforatum) and nevirapine is not recommended as it results in suboptimal antiretroviral concentrations and may be associated with loss of virologic response and development of resistance. Preliminary data suggest that this drug interaction occurs because St. John’s wort is a potent inducer of CYP isoenzymes responsible for metabolism of indinavir. St. John’s wort is an extract of hypericum and contains at least 7 different components that may contribute to its pharmacologic effects, including hypericin, pseudohypericin, and hyperforin. There is evidence that hypericum extracts can induce several different CYP isoenzymes, including CYP3A4 and CYP1A2, and also may induce the p-glycoprotein transport system. Therefore, it has been recommended that concomitant use of St. John’s wort and HIV protease inhibitors or NNRTIs metabolized by CYP isoenzymes be avoided.

    35. 35 PI and NNRTI Drug Interactions: Nevirapine (NVP) NVP (standard dose) + Indinavir (increase IDV to 1000 mg q8h or consider IDV/RTV) Ritonavir (dose RTV standard) Saquinavir (use with RTV) Nelfinavir (NFV dose standard) Amprenavir, fos-Amprenavir (no data) Lopinavir/r (use 4 caps bid or 3 tablets bid) Atazanavir (no data, most clinicians would use with ritonavir)

    36. 36 PI and NNRTI Drug Interactions: Efavirenz (EFV) EFV (standard dose) + Indinavir (increase IDV to 1000 mg q8 or consider IDV/RTV) Ritonavir (dose standard) Saquinavir (SQV not recommended as sole PI when used with EFV- use with RTV) Nelfinavir (dose standard) Amprenavir (add RTV 200 mg to standard APV of consider using APV/RTV 450/200 mg Fos-Amprenavir (use 1400 mg APV with 300 mg RTV once daily or 700 mg APV with 100 mg RTV bid Atazanavir (use ATV 300 mg with RTV 100 mg qd Lopinavir/r (use 4 caps of LPV/r bid or 3 tablets bid)

    37. 37 Nucleoside Interaction: Didanosine and Tenofovir ddI alone must be taken on an empty stomach TDF can be taken without regard to meals The Cmax and AUC of didanosine (buffered formulation or enteric coated) increased when given with tenofovir. Increases in didanosine concentrations could increase risk of adverse events, including pancreatitis and peripheral neuropathy Staggered or simultaneous administration of ddI EC 250mg with TDF, with or without a meal, results in similar drug exposures to ddI EC 400mg alone We have talked about significant interactions with PIs and other medications. Of note, an interaction exists between two nucleoside analogues: ddI and TDF. ddI is usually taken as 400 mg once daily on an empty stomach. TDF can be taken without regard to meals  The Cmax (highest level of the drug in the blood) and AUC (total amount of drug in blood) of didanosine (buffered formulation or enteric coated) increased when given with tenofovir. Increases in didanosine concentrations could increase adverse events, including pancreatitis and peripheral neuropathy. Administration of ddI EC 250mg with TDF staggered or simultaneously with or without a meal results in similar drug exposures to ddI EC 400mg alone Simultaneous administration of ddI EC 250 mg with TDF in the fasted and fed states resulted in a 14% increase and 11% decrease, respectively, in the ddI AUC. Clinically, no significant difference between the two states (fasted or fed) Clinical adverse events did not differ significantly when drugs given alone versus together. Tenofovir reduces the breakdown of ddI via inhibition of the purine nucleotide phosphorylase. Therefore, dose reduction of ddI to 250 mg is absolutely necessary. Moreover, TDF is primarily eliminated by a combination of glomerular filtration and active renal tubular secretion. There may be competition for elimination with ddI at the proximal tubule levelWe have talked about significant interactions with PIs and other medications. Of note, an interaction exists between two nucleoside analogues: ddI and TDF. ddI is usually taken as 400 mg once daily on an empty stomach. TDF can be taken without regard to meals  The Cmax (highest level of the drug in the blood) and AUC (total amount of drug in blood) of didanosine (buffered formulation or enteric coated) increased when given with tenofovir. Increases in didanosine concentrations could increase adverse events, including pancreatitis and peripheral neuropathy. Administration of ddI EC 250mg with TDF staggered or simultaneously with or without a meal results in similar drug exposures to ddI EC 400mg alone Simultaneous administration of ddI EC 250 mg with TDF in the fasted and fed states resulted in a 14% increase and 11% decrease, respectively, in the ddI AUC. Clinically, no significant difference between the two states (fasted or fed) Clinical adverse events did not differ significantly when drugs given alone versus together. Tenofovir reduces the breakdown of ddI via inhibition of the purine nucleotide phosphorylase. Therefore, dose reduction of ddI to 250 mg is absolutely necessary. Moreover, TDF is primarily eliminated by a combination of glomerular filtration and active renal tubular secretion. There may be competition for elimination with ddI at the proximal tubule level

    38. 38 Dosing Options for Tenofovir (TDF) and Didanosine (ddI) Buffered or EC In order to prevent ddI related side effects, the dose must be reduced to 250 mg for patients weighing > 60 kg Use ddI 200-250 mg in patients who weigh < 60 kg ddI buffered, dispersible available as 25, 50 and 100 mg tablets ddI EC available as 125mg, 200mg, 250mg and 400mg capsules, currently only buffered tablet is available in Ethiopia.In order to prevent ddI related side effects, the dose must be reduced to 250 mg for patients weighing > 60 kg Use ddI 200-250 mg in patients who weigh < 60 kg ddI buffered, dispersible available as 25, 50 and 100 mg tablets ddI EC available as 125mg, 200mg, 250mg and 400mg capsules, currently only buffered tablet is available in Ethiopia.

    39. 39 Antiretroviral/Food Interactions Take with food: Lopinavir (capsules or solution): ? 50-130% Saquinavir: 7 fold ? (fatty meal) Nelfinavir: 2-3 fold ? Ritonavir: 15% ? Itraconazole caps Atazanavir 70 % ? Ganciclovir ? up to 5% atovaquone 24% ? Avoid food: Amprenavir: ? 23% with high fat meal (regular food OK) Indinavir: 77% ? with high fat meal (light snack OK) ddI: 47% ? with meal Efavirenz: ? 79% high fat meal increases toxicity Rifampin: food may ? levels Itraconazole liquid Isoniazid Medications are recommended to be taken with food for one of two reasons: To ensure optimal absorption. e.g., Nelfinavir is best absorbed if it is taken with a meal or snack. In some instances, fat content of a meal may be an important factor affecting drug bioavailability. With lipid-soluble agents, ingestion of dietary fat results in formation of an oil or emulsion phase, which improves solubility. Ingesting a fatty meal also promotes secretion of gastric fluids, which in turn may lower gastric pH, delay stomach emptying, and decrease GI transit rates. e.g. Absorption of SQV is significantly increased when taken within 2 hours of a high-fat meal. Itraconazole caps can be taken with food or cola to increase absorption. Administration of a single 400 mg dose of ATZ with a light meal resulted in a 70% increase in AUC. Ganciclovir is poorly absorbed, if taken with food, levels are increased at best 5%. Atovaquone must be taken with a fatty meal to ensure absorption (23 g fat: 610 kcal). Amprenavir can be taken with or without meals; avoid a high fat meal which may decrease levels. IDV levels are reduced if taken with fat or high protein and should be taken on an empty stomach (at least 1 hour prior or 2 hours after a meal) or with a light, low-fat snack such as cereal with skim milk, toast and jam, fresh fruit, yogurt. ddI is destroyed by stomach acid, and therefore ddI tablets contain an antacid buffer. ddI tabs and EC caps should always be taken on an empty stomach since the presence of food interfere with action of the buffers. To reduce SE involving the stomach. Zidovudine does not need to be taken with food for adequate absorption. However, food may prevent or minimize the risk of stomach upset or nausea. INH should be taken on an empty stomach to attain peak concentration, however, it can be taken with food to decrease GI upset. Medications are recommended to be taken with food for one of two reasons: To ensure optimal absorption. e.g., Nelfinavir is best absorbed if it is taken with a meal or snack. In some instances, fat content of a meal may be an important factor affecting drug bioavailability. With lipid-soluble agents, ingestion of dietary fat results in formation of an oil or emulsion phase, which improves solubility. Ingesting a fatty meal also promotes secretion of gastric fluids, which in turn may lower gastric pH, delay stomach emptying, and decrease GI transit rates. e.g. Absorption of SQV is significantly increased when taken within 2 hours of a high-fat meal. Itraconazole caps can be taken with food or cola to increase absorption. Administration of a single 400 mg dose of ATZ with a light meal resulted in a 70% increase in AUC. Ganciclovir is poorly absorbed, if taken with food, levels are increased at best 5%. Atovaquone must be taken with a fatty meal to ensure absorption (23 g fat: 610 kcal). Amprenavir can be taken with or without meals; avoid a high fat meal which may decrease levels. IDV levels are reduced if taken with fat or high protein and should be taken on an empty stomach (at least 1 hour prior or 2 hours after a meal) or with a light, low-fat snack such as cereal with skim milk, toast and jam, fresh fruit, yogurt. ddI is destroyed by stomach acid, and therefore ddI tablets contain an antacid buffer. ddI tabs and EC caps should always be taken on an empty stomach since the presence of food interfere with action of the buffers. To reduce SE involving the stomach. Zidovudine does not need to be taken with food for adequate absorption. However, food may prevent or minimize the risk of stomach upset or nausea. INH should be taken on an empty stomach to attain peak concentration, however, it can be taken with food to decrease GI upset.

    40. 40 Avoid Antacids PIs Indinavir (fos)amprenavir Amprenavir Atazanavir Ketoconazole Fluoroquinolones Isoniazid Dapsone Zalcitabine Delavirdine It is essential to avoid co-administration of antacids with the following medications to ensure absorption. Protease inhibitors: Amprenavir and antacid administration have not been specifically studied. However, based on data available between antacids and other protease inhibitors, it is recommended that these drugs be taken at least one hour apart (Prod Info Agenerase, 2000). Omeprazole is contraindicated with atazanavir, only ranitidine given as 300 mg 12 hours apart from atazanavir can be used as an acid suppressing drug. Fluoroquinolones: Concurrent administration of ciprofloxacin with magnesium/aluminum antacids should be avoided. Ciprofloxacin may be taken two hours before or six hours after taking an antacid. An H2 blocker such as ranitidine may be an alternative to antacids in some clinical situations. Ketoconazole requires an acid pH for adequate absorption (drugs and food may change the acidity of the gut and decrease absorption). Aluminum antacids decrease the absorption of isoniazid (Hurwitz & Schlozman, 1974). Recommend taking antacids at least two hours after taking isoniazid. Absorption of dapsone is dependent upon an acidic pH and may be diminished with other drugs, such as ddI tablets, containing buffersIt is essential to avoid co-administration of antacids with the following medications to ensure absorption. Protease inhibitors: Amprenavir and antacid administration have not been specifically studied. However, based on data available between antacids and other protease inhibitors, it is recommended that these drugs be taken at least one hour apart (Prod Info Agenerase, 2000). Omeprazole is contraindicated with atazanavir, only ranitidine given as 300 mg 12 hours apart from atazanavir can be used as an acid suppressing drug. Fluoroquinolones: Concurrent administration of ciprofloxacin with magnesium/aluminum antacids should be avoided. Ciprofloxacin may be taken two hours before or six hours after taking an antacid. An H2 blocker such as ranitidine may be an alternative to antacids in some clinical situations. Ketoconazole requires an acid pH for adequate absorption (drugs and food may change the acidity of the gut and decrease absorption). Aluminum antacids decrease the absorption of isoniazid (Hurwitz & Schlozman, 1974). Recommend taking antacids at least two hours after taking isoniazid. Absorption of dapsone is dependent upon an acidic pH and may be diminished with other drugs, such as ddI tablets, containing buffers

    41. 41 Alternative Medicine Some alternative medicine or herbal therapies have been shown to interact with ART Pharmacists and providers must be aware of the potential interaction should their patient wish to take alternative medicine The interactions may increase or decrease ART levels leading to either an increase in toxicity or loss of efficacy St John™s Wort is an herbal preparation used to treat depression. Its active constituent, hypercillin has strong induction properties. St. John™s wort has been reported to induce both CYP3A4 and p-glycoprotein. IDV plasma concentrations were decreased by up to 50 % (Piscitelli 2000) and NVP by up to 35 % (de Maat 2001). For this reason, St. John™s wort is contraindicated in combination with PIs and NNRTIs and patients should be advised about this. Subtherapeutic plasma concentrations of SQV (administered 1200 mg TID) were also observed in combination with garlic supplements. Allicin, one active agent of garlic capsules, decreases trough concentrations of unboosted SQV by up to 49 % and AUC by 51 %. After discontinuing garlic intake, 60-70 % of SQV plasma con-centrations returned to baseline levels (Piscitelli 2002). In a PK study using 7 patients, reduced plasma concentrations of IDV were measured in combination with un boosted IDV and 1000 mg vitamin C. Minimum con-centrations of IDV decreased by about 32 % (Slain 2003). Potential inducing effects of ginseng have been shown in vitro (Henderson 1999); studies are warranted to establish these effects in patients. St John™s Wort is an herbal preparation used to treat depression. Its active constituent, hypercillin has strong induction properties. St. John™s wort has been reported to induce both CYP3A4 and p-glycoprotein. IDV plasma concentrations were decreased by up to 50 % (Piscitelli 2000) and NVP by up to 35 % (de Maat 2001). For this reason, St. John™s wort is contraindicated in combination with PIs and NNRTIs and patients should be advised about this. Subtherapeutic plasma concentrations of SQV (administered 1200 mg TID) were also observed in combination with garlic supplements. Allicin, one active agent of garlic capsules, decreases trough concentrations of unboosted SQV by up to 49 % and AUC by 51 %. After discontinuing garlic intake, 60-70 % of SQV plasma con-centrations returned to baseline levels (Piscitelli 2002). In a PK study using 7 patients, reduced plasma concentrations of IDV were measured in combination with un boosted IDV and 1000 mg vitamin C. Minimum con-centrations of IDV decreased by about 32 % (Slain 2003). Potential inducing effects of ginseng have been shown in vitro (Henderson 1999); studies are warranted to establish these effects in patients.

    42. 42 Intoxicants Drug interactions involving recreational drugs are of particular concern Limited Data Amphetamine Ketamine Marijuana [Tetrahydrocanabinol (THC)] Alcohol LSD Cocaine Chat Drug interactions involving drugs of abuse are of particular concern due to an increased risk of life threatening side effects. However, not surprisingly, data in this area are sparse. Several fatal cases with regard to the simultaneous intake of RTV and ecstasy (MDMA) or gammahydroxybutyrate (GHB) have been reported in the literature (Hales 2000, Harrington 1999). Metabolic inhibition of amphetamines, MDMA and phencyclidine (PCP), can result in hypothermia, hypertension, arrhythmias, tachycardias and cramps. Reduced metabolism of ketamine can result in respiratory depression, hallucinations and unconsciousness. Increased LSD plasma concentrations are associated with hallucinations, psychosis, agitation and flash backs, and GHB with cramps, bradycardia, unconsciousness or respiratory depression. Cocaine, in the presence of NNRTIs, is metabolized more rapidly so that the liver toxic metabolite norcocaine can accumulate (Antoniou 2002). Marijuana (tetrahydrocannibinol, THC) probably has a lower interaction potential (Kosel 2002). We do not know the interaction of Chat with ARV, yet. More studies are needed. Moreover, the effects of recreational drugs on the metabolism of antiretrovirals (ARVs) are not well known and require careful consideration. When patients insist on using recreational drugs, the doses of some should be reduced by up to a quarter of the original dose. Alcohol should be avoided, breaks should be taken during dancing and continuous water intake is necessary to avoid dehydration. It is important to monitor for symptoms of recreational drug-associated adverse events.Drug interactions involving drugs of abuse are of particular concern due to an increased risk of life threatening side effects. However, not surprisingly, data in this area are sparse. Several fatal cases with regard to the simultaneous intake of RTV and ecstasy (MDMA) or gammahydroxybutyrate (GHB) have been reported in the literature (Hales 2000, Harrington 1999). Metabolic inhibition of amphetamines, MDMA and phencyclidine (PCP), can result in hypothermia, hypertension, arrhythmias, tachycardias and cramps. Reduced metabolism of ketamine can result in respiratory depression, hallucinations and unconsciousness. Increased LSD plasma concentrations are associated with hallucinations, psychosis, agitation and flash backs, and GHB with cramps, bradycardia, unconsciousness or respiratory depression. Cocaine, in the presence of NNRTIs, is metabolized more rapidly so that the liver toxic metabolite norcocaine can accumulate (Antoniou 2002). Marijuana (tetrahydrocannibinol, THC) probably has a lower interaction potential (Kosel 2002). We do not know the interaction of Chat with ARV, yet. More studies are needed. Moreover, the effects of recreational drugs on the metabolism of antiretrovirals (ARVs) are not well known and require careful consideration. When patients insist on using recreational drugs, the doses of some should be reduced by up to a quarter of the original dose. Alcohol should be avoided, breaks should be taken during dancing and continuous water intake is necessary to avoid dehydration. It is important to monitor for symptoms of recreational drug-associated adverse events.

    43. Pharmacokinetic Enhancement Step 4: Pharmacokinetic Enhancement (Slides 43-51) – 15 minutesStep 4: Pharmacokinetic Enhancement (Slides 43-51) – 15 minutes

    44. 44 Pharmacokinetic Enhancement Ritonavir used to “boost” Cmin and increase t˝ of other protease inhibitors Allows extended dosing intervals Decreases pill burden Reduces adverse effects May allow salvage in patients with resistance and reduced susceptibility Ritonavir (cont) Overcomes enzyme induction caused by other drugs Increase drug exposure Remove meal requirements Activity primarily via inhibition of CYP450 3A4 May also inhibit MDR-PGP efflux pumps We have talked about potential drug-drug interactions that lead to toxic effects of ARVs, let’s review how ARVs are used in a favorable way to enhance therapy. Pharmacokinetic (PK) enhancement is the concept of combining agents to improve ARV pharmacokinetics. PK enhancement takes advantage of enzyme inhibiting properties in order to improve the PK profile and/or bioavailability of one or more drugs. When certain drugs are combined, dosing regimens may be simplified, and often pill burden and/or food restrictions may be minimized. This can have a positive impact on adherence. E.g., when IDV and RTV are combined, the dose of IDV may be reduced to 400 mg twice daily and in the presence of RTV, IDV can be taken with food. With this combination, IDV peak levels are lower, which may potentially be associated with a reduced risk of nephrolithiasis. E.g. When RTV is combined with SQV, a lower dosage of RTV may be used, resulting in better tolerance than when RTV is taken at full dose. E.g. AddItive or synergistic antiviral effects may be observed when various ARVs are administered together. We have talked about potential drug-drug interactions that lead to toxic effects of ARVs, let’s review how ARVs are used in a favorable way to enhance therapy. Pharmacokinetic (PK) enhancement is the concept of combining agents to improve ARV pharmacokinetics. PK enhancement takes advantage of enzyme inhibiting properties in order to improve the PK profile and/or bioavailability of one or more drugs. When certain drugs are combined, dosing regimens may be simplified, and often pill burden and/or food restrictions may be minimized. This can have a positive impact on adherence. E.g., when IDV and RTV are combined, the dose of IDV may be reduced to 400 mg twice daily and in the presence of RTV, IDV can be taken with food. With this combination, IDV peak levels are lower, which may potentially be associated with a reduced risk of nephrolithiasis. E.g. When RTV is combined with SQV, a lower dosage of RTV may be used, resulting in better tolerance than when RTV is taken at full dose. E.g. AddItive or synergistic antiviral effects may be observed when various ARVs are administered together.

    45. 45 Pharmacokinetics Principles Let’s review Pharmacokinetics Principles to better understand PK enhancement with ritonavir The horizontal axis represents time and the vertical axis represents drug concentration Cmax is the maximum concentration of a drug. It correlates with some short-term side effects, e.g. nausea AUC is the area under the curve which represents overall drug exposureLet’s review Pharmacokinetics Principles to better understand PK enhancement with ritonavir The horizontal axis represents time and the vertical axis represents drug concentration Cmax is the maximum concentration of a drug. It correlates with some short-term side effects, e.g. nausea AUC is the area under the curve which represents overall drug exposure

    46. 46 Pharmacokinetics Principles (2) The Cmin is the minimum, or trough concentration. It occurs at the end of the dosing interval and correlates with anti-HIV effect for all PIsThe Cmin is the minimum, or trough concentration. It occurs at the end of the dosing interval and correlates with anti-HIV effect for all PIs

    47. 47 Pharmacokinetic Rationale for Dual Protease Inhibitor Therapy When a single PI is used, its peaks may reach well above the desired concentration for effectiveness and this may lead to drug toxicity. When PIs are used together, you are able to achieve lower peak levels Reduces the chance of side effects Achieves higher trough levels, increasing potency and reducing the chance of viral replication.

    48. 48 An Example of Ritonavir Boosting: Indinavir/Ritonavir BID PK Study This graph depicts the drug levels achieved with a protease inhibitor alone versus a ritonavir boosted PI. The black line represents the levels for the PI Indinavir when given alone, which is usually administered on empty stomach three times daily. The red, blue and gray curves depict the level of indinavir when given with differing doses of ritonavir and food. Note that when indinavir is given with ritonavir, it is able to be given with food and boosting with ritonavir permits BID dosing, that improves patient adherence. But currently ritonavir enhanced Indinavir is not available in Ethiopia.This graph depicts the drug levels achieved with a protease inhibitor alone versus a ritonavir boosted PI. The black line represents the levels for the PI Indinavir when given alone, which is usually administered on empty stomach three times daily. The red, blue and gray curves depict the level of indinavir when given with differing doses of ritonavir and food. Note that when indinavir is given with ritonavir, it is able to be given with food and boosting with ritonavir permits BID dosing, that improves patient adherence. But currently ritonavir enhanced Indinavir is not available in Ethiopia.

    49. 49 Steady State IDV Plasma Profile after IDV + RTV 400 mg Q12H with Food Over time the levels of indinavir remain more constant when dosed with ritonavir. IC90 refers to inhibitory concentration of IDV by 90%.Over time the levels of indinavir remain more constant when dosed with ritonavir. IC90 refers to inhibitory concentration of IDV by 90%.

    50. 50 Dual Protease Inhibitors Saquinavir + ritonavir SQV 400mg/RTV 400mg BID SQV 1000mg/RTV 100mg BID SQV 1600mg/RTV 100mg QD Indinavir + ritonavir IDV 400mg/RTV 400mg BID IDV 800mg/RTV 100-200mg BID Amprenavir + ritonavir APV 600mg/RTV 100mg BID APV 1200mg/RTV 200mg QD Lopinavir + ritonavir 3 Co-formulated capsules BID or 2 tablets BID Atazanavir + ritonavir ATV 300mg/RTV 100mg QD Fosamprenavir + ritonavir F-APV 700mg/RTV 100mg BID F-APV 1400mg/RTV 200mg QD Common doses of ritonavir boosted protease inhibitors. Reference notes: RTV +SQV increases Cmax, Cmin, AUC (RTV dose does not have large impact, mostly affects absorption) RTV +IDV increases Cmin and AUC, no real effect on Cmax (as you increase the dose, you increase effects on all parameters). Mostly affects elimination, metabolism by CYP3A4 or by p-glycoprotein RTV +AMP increases Cmin and AUC, further increases in RTV dose does little to increase AUC RTV +NFV = no change as NFV is mostly metabolized by 2C19, 2D6. NFV metabolite increased, clinical significance unknown. Common doses of ritonavir boosted protease inhibitors. Reference notes: RTV +SQV increases Cmax, Cmin, AUC (RTV dose does not have large impact, mostly affects absorption) RTV +IDV increases Cmin and AUC, no real effect on Cmax (as you increase the dose, you increase effects on all parameters). Mostly affects elimination, metabolism by CYP3A4 or by p-glycoprotein RTV +AMP increases Cmin and AUC, further increases in RTV dose does little to increase AUC RTV +NFV = no change as NFV is mostly metabolized by 2C19, 2D6. NFV metabolite increased, clinical significance unknown.

    51. 51 The Role of a Pharmacist in Drug Interactions Pharmacists must be knowledgeable about potential drug-drug, drug-food interactions Pharmacists should question a patient about their current medications whenever filling a prescription that is new for them Patients should be educated that drug interactions can also occur if they stop or receive a change in dose of their medications Pharmacists should ask patients about their use of herbal preparations as they can interact with ARV therapy

    52. Drug Interaction Case Studies Step 5: Case Studies (Slides 52-71) – 60 minutesStep 5: Case Studies (Slides 52-71) – 60 minutes

    53. Case 1

    54. 54 Case Study: Endalk Endalk is 45 year-old HIV+ male presenting for routine follow-up. He has been on HAART for two years CD4 count: 480 cells/mm3 HIV RNA < 50 copies/mL. He comes into your pharmacy after seeing a physician for his migraines. He is glad to try a new medication as his headaches have been a problem for years. He is so distraught about them that he has begun to take an herbal product to help with his mood

    55. 55 Case Study: Endalk (2) You ask him his current medication regimen, which is: Nevirapine 200 mg bid Lamivudine 150mg bid Zidovudine 300 mg bid An herbal medicine when he feels “down” New medications prescribed today: Ergotamine + caffeine

    56. 56 Case Study: Endalk (3) Which of the following combinations represents a potential drug-drug interaction? Nevirapine and herbal medicine Zidovudine and ergotamine Ergotamine and nevirapine Caffeine and zidovudine C is the correct answer However, you should inquire as to which herbal medicine he takes as some can interact with ARVs. For example, St. John’s Wort is a 3A4 inducer. It is not widely available in Ethiopia, however, if a patient indicates they take herbal medicine with ARVs, they should be closely monitored for virologic failure or toxicity. It is difficult to predict drug interactions between ARVs and herbal medicines. The next slide contains more about interaction with herbal medicines C is the correct answer However, you should inquire as to which herbal medicine he takes as some can interact with ARVs. For example, St. John’s Wort is a 3A4 inducer. It is not widely available in Ethiopia, however, if a patient indicates they take herbal medicine with ARVs, they should be closely monitored for virologic failure or toxicity. It is difficult to predict drug interactions between ARVs and herbal medicines. The next slide contains more about interaction with herbal medicines

    57. 57 Case Study: Endalk (4) Herbal medicines Concomitant use with herbal medicine can decrease serum levels of NNRTIs. e.g. St. John's Wort can increase the oral clearance of nevirapine (viramune) by 35% Sub-therapeutic concentrations are associated with therapeutic failure, development of viral resistance, and development of drug class resistance e.g. St. John's Wort induces intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and intestinal P-glycoprotein/MDR-1, a drug transporter Avoid use with any NNRTI or PI Nevirapine is metabolized by CYP3A4. Competition for this pathway could result in inhibition of ergot metabolism, creating the potential for ergotism (nausea, vomiting, vasospastic ischemia) This is true for EFV as well: Efavirenz and ergot derivatives are both metabolized by the cytochrome P450 3A4 enzyme system. Competition for this pathway could result in inhibition of ergot metabolism, creating the potential for ergotism (nausea, vomiting, vasospastic ischemia). Nevirapine is metabolized by CYP3A4. Competition for this pathway could result in inhibition of ergot metabolism, creating the potential for ergotism (nausea, vomiting, vasospastic ischemia) This is true for EFV as well: Efavirenz and ergot derivatives are both metabolized by the cytochrome P450 3A4 enzyme system. Competition for this pathway could result in inhibition of ergot metabolism, creating the potential for ergotism (nausea, vomiting, vasospastic ischemia).

    58. 58 Case Study: Endalk (5) What would you recommend to Endalk for his depression? What would you recommend to him for his migraines? You should refer him to see his provider about his depression. Untreated depression may lead to non-adherence and treatment failure as well as poor quality of life. Amitriptyline is used commonly in Ethiopia. If used with nevirapine, Amitriptyline levels may be decreased Patients on either a PI or NNRTI should be treated for migraines with sumatriptan, NSAIDs, paracetamol Nevirapine may gradually reduce the serum levels and effect of amitriptyline. The results of this interaction may be variable. He should be monitored for altered tricyclic antidepressant effect. This is unlike the interaction with PIs which could increase amitriptyline levels. You should refer him to see his provider about his depression. Untreated depression may lead to non-adherence and treatment failure as well as poor quality of life. Amitriptyline is used commonly in Ethiopia. If used with nevirapine, Amitriptyline levels may be decreased Patients on either a PI or NNRTI should be treated for migraines with sumatriptan, NSAIDs, paracetamol Nevirapine may gradually reduce the serum levels and effect of amitriptyline. The results of this interaction may be variable. He should be monitored for altered tricyclic antidepressant effect. This is unlike the interaction with PIs which could increase amitriptyline levels.

    59. Case 2

    60. 60 Case Study: Sara Sara is a 41 year-old female with esophageal candida and has just completed a 10 day course of fluconazole. She has lost weight because symptoms of thrush made it difficult to swallow. She weighs 62 kg. She is to begin ARV therapy today. She comes to your pharmacy to fill her prescriptions. She qualifies for treatment because she has Grade IV disease in the WHO staging system.She qualifies for treatment because she has Grade IV disease in the WHO staging system.

    61. 61 Case Study: Sara (2) She presents you with the following: Zidovudine 300 mg bid Stavudine 40 mg bid Nevirapine 200 mg once daily for the first 2 weeks, then increase to 200 mg bid Cotrimoxazole DS, 1 tablet daily Is this an appropriate regimen for her? Can you identify any possible drug interactions? No, this regimen is not appropriate for her. ZDV should never be used with D4T as they compete for intracellular phosphorylation The first line choice of nucleoside therapy should be ZDV + 3TC or D4T + 3TC in combination with nevirapine No, this regimen is not appropriate for her. ZDV should never be used with D4T as they compete for intracellular phosphorylation The first line choice of nucleoside therapy should be ZDV + 3TC or D4T + 3TC in combination with nevirapine

    62. 62 Case Study: Sara (3) How would you communicate the change that you recommended to the physician who wrote the prescription? What would you say to the physician? The pharmacist must form a relationship with the providers who write prescriptions for ART. Communication may be made by phone, in person or through the patient. Whichever way is most efficient and effective for making the change is acceptable. Always be professional when communicating with the physician. Remember that you are sharing information with another health care provider. Explain about the pharmacokinetic interactions between zidovudine and stavudine; the possible overlapping toxicity of cotrimoxazole and zidovudine with regard to bone marrow suppression; and the incidence of rash if cotrimoxazole and nevirapine are prescribed at the same time.The pharmacist must form a relationship with the providers who write prescriptions for ART. Communication may be made by phone, in person or through the patient. Whichever way is most efficient and effective for making the change is acceptable. Always be professional when communicating with the physician. Remember that you are sharing information with another health care provider. Explain about the pharmacokinetic interactions between zidovudine and stavudine; the possible overlapping toxicity of cotrimoxazole and zidovudine with regard to bone marrow suppression; and the incidence of rash if cotrimoxazole and nevirapine are prescribed at the same time.

    63. Case 3

    64. 64 Case Study: Lake Lake, a 50 year-old male who has been HIV+ for 5 years and is stable on therapy, presents to the clinic to get more medication to treat his thrush He has been taking his brother’s medication, which seemed to help at first and then stopped working. He would like to get some more to clear the white plaques on his tongue

    65. 65 Case Study: Lake (2) Oral Thrush

    66. 66 Case Study: Lake (3) His current ARV regimen is: Nevirapine 200 mg bid Stavudine 40 mg bid Lamivudine 150 mg bid He has one pill of his brother’s medication left. The physician brings it to your pharmacy to determine what medication it is You identify the tablet as ketoconazole 200 mg

    67. 67 Case Study: Lake (4) Is this an appropriate medication to use with his current ARV regimen? What are some counseling points for this patient? No, this is not an appropriate therapy for his thrush Ketoconazole interacts with nevirapine Ketoconazole levels are decreased by 63% Nevirapine levels are increased by 15-30% They should not be co-administered An alternative is a topical antifungal such as nystatin suspension or miconazole oral gel Ketoconazole levels are decreased by 63% and this is most likely the reason that his thrush was not responding to the medication. Ketoconazole and nevirapine should not be given concurrently due to the decrease in ketoconazole concentrations. Coadministration of nevirapine (200 mg twice daily) with ketoconazole (400 mg once daily) to 22 HIV+ individuals resulted in a 63% reduction in ketoconazole AUC and a 40% reduction in Cmax. There was a 15–28% increase in plasma concentration of nevirapine. Although interaction studies have not been performed, antifungal medicinal products which are eliminated renally (e.g. fluconazole) may be substituted for ketoconazole. Studies using human liver microsomes indicated that ketoconazole significantly inhibited the formation of nevirapine hydroxylated metabolites. Topical therapy for thrush is always preferred as first line therapy before moving to oral tablets. Lamson M, Robinson P, Lamson M et al. The pharmacokinetic interactions of nevirapine and ketoconazole. 12th World AIDS Conference, 1998, abstract 12218. Viramune Summary of Product Characteristics, 2001, Boehringer Ingelheim International. Viramune Product Information, 2000, Roxane Laboratories Inc. Counseling points Never share medication with others Always check with your physician or pharmacist BEFORE starting any medications on your own Prescription OTC Herbal No, this is not an appropriate therapy for his thrush Ketoconazole interacts with nevirapine Ketoconazole levels are decreased by 63% Nevirapine levels are increased by 15-30% They should not be co-administered An alternative is a topical antifungal such as nystatin suspension or miconazole oral gel Ketoconazole levels are decreased by 63% and this is most likely the reason that his thrush was not responding to the medication. Ketoconazole and nevirapine should not be given concurrently due to the decrease in ketoconazole concentrations. Coadministration of nevirapine (200 mg twice daily) with ketoconazole (400 mg once daily) to 22 HIV+ individuals resulted in a 63% reduction in ketoconazole AUC and a 40% reduction in Cmax. There was a 15–28% increase in plasma concentration of nevirapine. Although interaction studies have not been performed, antifungal medicinal products which are eliminated renally (e.g. fluconazole) may be substituted for ketoconazole. Studies using human liver microsomes indicated that ketoconazole significantly inhibited the formation of nevirapine hydroxylated metabolites. Topical therapy for thrush is always preferred as first line therapy before moving to oral tablets. Lamson M, Robinson P, Lamson M et al. The pharmacokinetic interactions of nevirapine and ketoconazole. 12th World AIDS Conference, 1998, abstract 12218. Viramune Summary of Product Characteristics, 2001, Boehringer Ingelheim International. Viramune Product Information, 2000, Roxane Laboratories Inc. Counseling points Never share medication with others Always check with your physician or pharmacist BEFORE starting any medications on your own Prescription OTC Herbal

    68. Case 4

    69. 69 Case Study: Micahel Micahel is a 50 year-old male patient who has just completed 9 months of TB therapy (regimen was rifampicin and isoniazid along with pyridoxine) 3 weeks ago. He has also been on ARVs (EFV 800 mg qhs, 3TC 150 mg bid and ZDV 300 mg bid) during this time. He presents with a bloody nose and bruises on his arm Other current medications include: Coumadin for atrial fibrillation Atenolol for blood pressure

    70. 70 Case Study: Micahel (2) What do you suspect has happened? How should this patient have been counseled before the TB medication was discontinued? Enzyme inducers, such as rifampicin, gradually reduce the response to oral anticoagulants, usually over 1-2 weeks (maybe sooner with rifampicin). The offset of the effect usually takes place gradually over 2-3 weeks. Since the patient has just discontinued taking rifampicin, the response to his coumadin will presumably increase, leading to supra-therapeutic levels The patient should have been counseled to be aware of the result of the discontinuation of his TB meds and the effect that it could have on his warfarin Leads to supratherapeutic response to warfarin Increases the risk of bleeding and bruising He should have had his PT/INR measured to monitor his anticoagulation His dose of warfarin will need to be adjusted to achieve the desired therapeutic range Enzyme inducers, such as rifampicin, gradually reduce the response to oral anticoagulants, usually over 1-2 weeks (maybe sooner with rifampicin). The offset of the effect usually takes place gradually over 2-3 weeks. Since the patient has just discontinued taking rifampicin, the response to his coumadin will presumably increase, leading to supra-therapeutic levels The patient should have been counseled to be aware of the result of the discontinuation of his TB meds and the effect that it could have on his warfarin Leads to supratherapeutic response to warfarin Increases the risk of bleeding and bruising He should have had his PT/INR measured to monitor his anticoagulation His dose of warfarin will need to be adjusted to achieve the desired therapeutic range

    71. 71 Case Study: Micahel (3) If it is necessary to use enzyme inducers and drugs that are substrates of those enzymes. Monitor for altered response if the inducer is initiated, discontinued, or changed in dosage What other drug interactions should be addressed today? Now that the patient is no longer taking rifampicin, the dose of his efavirenz should be reduced to 600 mg qhs This could be done now as he has been off rifampicin for 3 weeks, the required time for this effect to offset Now that the patient is no longer taking rifampicin, the dose of his efavirenz should be reduced to 600 mg qhs This could be done now as he has been off rifampicin for 3 weeks, the required time for this effect to offset

    72. 72 Key Points Pharmacokinetic interactions refer to what the body does to the drug Pharmacodynamic interactions refer to what the drug does to body A drug interaction can occur whenever a medication is started or discontinued or whenever a dose is changed. Pharmacists play a critical role in detecting drug interactions before they happen Step 6: Key Points, Questions (Slides 72-74) – 5 minutes Review these key points with participants Ask for questions about this unit. Step 6: Key Points, Questions (Slides 72-74) – 5 minutes Review these key points with participants Ask for questions about this unit.

    73. 73 Key Points (2) Pharmacists must be knowledgeable about potential drug-drug and drug-food interactions Pharmacists should question a patient about their current medications whenever filling a new prescription, changing dose, or discontinuing a medication Patients should be educated that drug interactions can also occur if they stop or change a medication or dose

    74. 74 Key Points (3) Pharmacists should ask patients about their use of herbal preparations as they can interact with ARV therapy Pharmacokinetic enhancement combines agents from different classes or various agents from similar classes to: Improve ARV pharmacokinetics Improve adherence Minimize side effects Enhance antiviral activity

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