Therapeutic Drug Monitoring (TDM) Lesson: Pharmacology Variations Explained

1. Pakistan Society Of Chemical PathologistsDistance Learning Programme In Chemical Pathology(DLP-2)Lesson No 18Therapeutic Drug Monitoring(TDM)By Brig Aamir IjazMCPS, FCPS, FRCP (Edin), MCPS-HPEHOD and Professor of Pathology / AFIP Rawalpindi

2. Part IMCQs (One Best Type)

3. What is TDM • Monitoring of therapeutic drugs involves measuring drug concentration in plasma, serum or blood. • It is used to individualize dosage so that drug concentration can be maintained within a target range aiming to enhance drug efficacy, reduce toxicity or assist with diagnosis.

5. Q.1: A medicine showed response rates of 73.5% and 41.3% in two different individuals of similar physical characteristics and disease pattern. The sub-branch of pharmacology which can be most helpful in explaining such individual variations is called: a. Pharmacodynamics b. Pharmacogenomics c. Pharmacognosy d. Pharmacokinetics e. Pharmacotherapeutics b. Pharmacogenomics

6. Branches/Divisions of Pharmacology Slides courtesy of DrSabihaWaseem, Canada

7. Pharmcodynamics • Greek: dynamis, power • Deals with biological effects (pharmacologic and toxic) • Also includes mechanism of action of the drug

8. Pharmacokinetics • Greek: kinesis, movement • Pertaining to handling of drug by the body i.e. movement of the drug in, through and out of the body to achieve drug action. • Four major processes; absorption, distribution, biotransformation and excretion

9. Pharmcotherapeutics Application of pharmacological information together with knowledge of the disease for its prevention or cure i.e. use of drugs in treatment of disease

10. Pharmacognosy It is the study of medicines derived from natural sources. It is also defined as "the study of the physical, chemical, biochemical and biological properties of drugs, drug substances or potential drugs or drug substances of natural origin as well as the search for new drugs from natural sources." It is also defined as the study of crude drugs.

11. Pharmacogenomics and Pharmacogenetics Pharmacogenomics refers to the general study of the many different genes that determine drug behavior. Pharmacogeneticsrefers to the study of inherited differences (variation) in drug metabolism and response.

12. Q 2.For TDM, a steady state is required. The steady state of most of the drugs is achieved when: a. Drug starts being eliminated rapidly b. Drug concentration at site of action equals with serum drug concentration. c. Equal distribution of drug has been carried out in all body fluids d. Five to seven identical doses have been administered e. Serum drug concentration is less than the minimum effective concentration • Five to seven identical doses have been administered

13. Steady State of Drugs Slides courtesy of Dr Qurat-Ul-Ain, AFIP Rwp Please see Slide after Question No 7

14. Q. 3: Bioavailability of a drug is one of the most important aspects of efficacy of a drug. Which of the following factors leads to the greatest bioavailability of a drug: a. Active gastrointestinal transporters b. Co-administration of morphine c. Low first pass metabolism d. pH of the gastrointestinal tract greater than the Pka of the acidic drugs e. Simultaneous use of absorptive resins c. Low first pass metabolism

15. Bioavailability Slides courtesy of Dr Saima Bashir, AFIP Rwp

16. Definition of Bioavailability • The amount of drug in the formulation that the system of patient can absorb. • Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.

17. Factors affecting Bioavailability • Pharmaceutical factors: Related to different properties of drugs like particle size. • GI transit time • First pass metabolism • Presence of other agents • Disease state • Enterohepatic cycling

19. Determination of bioavailability • Bioavailabilty is determined by comparing the rate and extent of absorbtion of drug from oral form to the data of referance standard (IV form) The area under the plasma concentration-time curve of an equivalent dose of IV and oral form

20. Significance of bioavailability • Bioavailability calculation is significant for drugs in conditions like • Drugs having low therapeutic index • Drugs whose peak levels are required for effects of drugs like antibiotics • Drugs which undergo first pass metabolism • Formulations that give sustained release of drug

21. Q.4:A 62 year male, who is a known patient of ESRD, is taking phenytoin for epilepsy. His recent serum phenytoin estimation shows levels within therapeutic range but his physician is not satisfied with the result as he thinks patient is developing clinical signs suggestive of phenytoin over-dosage. He has referred the patient to you for expert advice. The most helpful laboratory investigation for this patient will be: a. ALT b. eGFR c. GFR by creatinine clearance d. Serum free phenytoin level e. SNP analysis d. Serum free phenytoin level

22. Protein Binding of Drugs Slides courtesy of Dr SafiaAsim, AFIP Rwp

23. Protein Binding of Drugs • Many drugs interact with plasma or tissue proteins or with other macromolecules, such as melanin and DNA, to form a drug– macromolecule complex. • The formation of a drug protein complex is often named drug–protein binding

25. Types of Drug-Protein Bindings • Irreversible drug–protein binding is usually a result of chemical activation of the drug, which then attaches strongly to the protein or macromolecule by covalent chemical bonding. Irreversible drug binding accounts for certain types of drug toxicity that may occur over a long time period. For example, the hepatotoxicity of high doses of acetaminophen is due to the formation of reactive metabolite intermediates that interact with liver proteins. • Reversible drug–protein binding implies that the drug binds the protein with weaker chemical bonds, such as hydrogen bonds or vander Waals forces.

26. Proteins Involved in Drug-Protein Bindings • The proteins commonly involved in binding with drugs are albumin, lipoproteins, and α1-acid-glycoprotein (AGP). • Acidic and neutral compounds will tend to bond with albumin, which is basic, while basic substances will primarily bind to the acidic AGP molecule.

27. Bound and Unbound Fractions of Drugs • A drug in blood exists in two forms: bound and unbound • It is the unbound fraction which exhibits pharmacologic effects. It is also the fraction that may be metabolized and or excreted. • For example, the "bound fraction" of the anticoagulant warfarin is 97%. This means that of the amount of warfarin in the blood, 97% is bound to plasma proteins. The remaining 3% (the fraction unbound) is the fraction that is actually active and may be excreted. The bound drug is kept in the blood stream while the unbound component may be metabolized or excreted, making it the active part

28. Drug Interaction due to Protein Bindings • Using 2 drugs at the same time may affect each other's fraction unbound. • For example, assume that Drug A and Drug B are both protein- bound drugs. • If Drug A is given, it will bind to the plasma proteins in the blood. • If Drug B is also given, it can displace Drug A from the protein, thereby increasing Drug A's fraction unbound. • This may increase the effects of Drug A, since only the unbound fraction may exhibit activity.

29. Q: 5. A 36 year old lady underwent renal transplant. She has been advised TDM of Cyclosporine. The ideal blood sample should be: a. Freshly collected serum b. Plasma collected in citrate tube c. Plasma collected in lithium heparin tube’ d. Plasma collected in Sodium Fluoride tube e. Whole blood collected in EDTA tube e. Whole blood collected in EDTA tube

30. Q. 6: In a Chemical Pathology laboratory, there is problem of poor clinical correlation of patients` reports of TDM of antiepileptics. Internal Quality Control and External Quality Assurance results are quite acceptable. All of the following measures may be helpful in solving this problem EXCEPT: a. Decreasing storage time of the samples b. Establishing procedures for using saliva as sample c. TDM of most of the drugs during steady state d. Proper timing of the sample collection e. Use of sample tubes with separation gel e. Use of sample tubes with separation gel

31. Sampling for TDM Slides courtesy of Dr SumbalNida, AFIP Rwp

32. Prerequisites Before drawing a sample we must know • The purpose of TDM that is whether it is being carried out to check toxicity, compliance, efficacy or to establish the drug dosing regimen. • The pharmakokinetics and pharmodynamics of the drug under study. • The different factors that affect the analysis of the drug

33. Important Issues related to Samples for TDM • Each laboratory should inform the health care providers about the therapeutic and toxic concentrations, required sample volume, and collection tube specifications. • Guidelines should be available for ideal individual drug monitored. • The time and date of collection of the drug sample and of the last dose should be noted.

34. Q. 7: During the steady state of the drugs samples for TDM are commonly taken just before the scheduled dose to estimate the ‘trough levels’ of the drug. The rationale for using this sampling regimen is to: a. Cater for the drugs with longer half-life b. Ensure maximum efficacy c. Ensure minimum toxicity d. Include drugs with non-linear kinetics e. Minimize inter-patient variability e. Minimize inter-patient variability

35. Steady State of Drugs Slides courtesy of Dr Qurat-Ul-Ain, AFIP Rwp

36. What is Steady State • Steady state is the point where the amount of drug entering in the systemic circulation is equal to the amount being eliminated • Each dose has identical profile of drug concentration versus time and still have a trough (Cmin) and peak (Cmax) • The time to reach steady-state concentrations is dependent on • Half life-shorter half-life results in lesser time to steady state • Volume of distribution (VD)– large VD results in longer half life and more time is required to reach steady state • Clearance- rapid clearance leads to shorter time to steady state due to shorter half life

37. How Drugs reach Steady State • Steady state (>95% of Css) is achieved by 5 doses with dosing interval equal to half-life of the drug.  • Similarly, at the end of therapy 5-7 half-lives must be passed to eliminate > 95% of drug • For drugs with very long half life initial bolus dose is administered to bring plasma concentration close to steady state followed by maintenance dose

39. Clinical Implications • Ideal sampling for TDM is at trough • To minimizes inter-patient variability in drug disposition • To improve reliability of comparison of a single plasma value with population therapeutic range • Random sampling • Suitable for drugs with less fluctuation between trough and peak concentration e.g. • Very long half-lives • Extended release formulation

40. Q. 8. Michaelis-MentenKinetics is commonly used to study the metabolism of the drugs. Most of the drugs follow First-Order Metabolism but some drugs/substances do follow Zero-Order Metabolism. Which of the following statements best describes Zero-Order Metabolism ? a. A set fraction of drug is metabolized per unit time b. Availability of enzyme to bind drug is the rate limiting factor c. Available metabolic capacity exceeds the amount of drug present d. Rate of metabolism is proportional to the concentration of drug e. The drug kinetics are linear during steady state b. Availability of enzyme to bind drug is the rate limiting factor

41. First Order and Zero Order Kinetics Slides courtesy of DrUzma Ansari, AFIP Rwp

42. Michaelis – Menten Equation Describes the rate of enzyme metabolism of drug dC/dt = Vmax C / Km+C C = drug concentration Vmax = maximum rate of drug elimination Km = drug concentration at which rate of elimination is half maximum

43. First Order Kinetics • Constant fractionof drug is eliminated per unit time. • Concentration of drug is relatively low , such that it does not approach the saturation of its elimination mechanisms. • Also called linear kinetics because log C plotted versus time is a linear function. • Biological half life is constant for drugs with first order kinetics

44. Zero Order Kinetics Constant amount of drug is eliminated per unit time , independent of blood drug concentration Concentration of drug is relatively high, such that it exceeds the saturation of its elimination mechanisms. Also called non - linear or dose dependent kinetics. Biological half life is not constant for drugs with zero order kinetics

46. Q. 9:A 49 year female is taking anti-depressant. She has been advised TDM of this drug, because initially the drug showed clinical improvement but when the dose was increased above a certain threshold level the clinical response reversed and symptoms re-appeared. The physician told the patient that this drug is notorious for this phenomenon called ‘An inverted U correlation’. The patient is most probably using: a. Amitriptyline b. Clomipramine c. Desipramine d. Imipramine e. Nortriptyline e. Nortriptyline

47. TDM of Antidepressants Slides courtesy of DrAmjadPervaiz, AFIP Rwp

48. TDM of Antidepressants • TDM is highly recommended for most tricyclic antidepressants to monitor risk of toxicity • For some tricyclic antidepressants e.g. imipramine, desipramine ,nortriptyline, serum conc. does correlate with clinical effects, TDM can be used for monitoring efficacy of these drugs. • TDM is not recommended for SSRIs because they have a wide therapeutic index.

49. Sampling Times And Intervals • The half-lives of TCA,s are approximately 24 h • They attain steady state in approximately 5-7 days • Most patients take a single evening dose • Blood samples are taken to measure trough level, 12-14 h after the last dose • Serum or plasma can be used, serum is preferred as it allows greater ease of extraction

50. Q. 10: A 32 year male patient is taking antiepileptic for epilepsy but TDM of the drug is not properly correlated with the patient`s clinical features in spite of proper compliance and sampling time. Important characteristics of the drug include non-linear kinetics of the drug in therapeutic dose, drug-drug interaction and cross reactivity of immunoassays with its metabolites: The patient is most probably using: a. Carbamazepine b. Clonazepam c. Phenytoin d. Primadone e. Valproic acid c. Phenytoin