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Antiretroviral Combinations

Antiretroviral Combinations. James A Zachary MD LSU Health Sciences Center HIV Outpatient Clinic December 13, 2004 http://HIVManagement.org. Objectives. Review rationale for combinations Review basis of protease inhibitor interactions Review specific combinations (mainly PI)

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Antiretroviral Combinations

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  1. Antiretroviral Combinations James A Zachary MDLSU Health Sciences CenterHIV Outpatient ClinicDecember 13, 2004 http://HIVManagement.org

  2. Objectives • Review rationale for combinations • Review basis of protease inhibitor interactions • Review specific combinations (mainly PI) • Review what is not known • Final recommendations

  3. Benefits of Boosting • Improved adherence • Decrease pill burden • Decrease dosing frequency • Decrease meal dependence • Improve efficacy • Improved adherence • Improved levels of protease inhibitors • Levels out interindividual variations • Compensates for the effects of inducers

  4. Problems of Boosting • Multiple drug-drug interactions • Increased serum lipid & fat redistribution side effects • Increased side effects • Abdominal pain • Diarrhea • Nausea • Hepatitis • Perioral paresthesia • Increased number of prescribed medications • Need to refrigerate medication (ritonavir)

  5. Pharmacology • Protease inhibitors and NNRTIs are primarily metabolized via cytochrome P-450 family of enzymes • P-450 enzymes • Primarily in liver but also in apical enterocytes • Multiple metabolic pathways by which these drugs are metabolized, with the most significant being CYP3A4

  6. P-450 • Inhibition • Inhibition can lead to increases in drug levels of agents that are normally metabolized through CYP450 • Can occur after the first dose of an enzyme inhibitor • Ritonavir > saquinavir = lopinavir = indinavir > amprenavir • A flavinoid component which is peculiar to grapefruit (narangin or narangenin) blocks CYP4503A4 metabolism at the enzyme level

  7. P-450 • Induction • Leads to a decrease in serum concentrations in drug levels with the time frame for maximal induction being about 2 weeks • Ritonavir, nelfinavir, and lopinavir

  8. P-450 • Mixed induction-inhibition • Complex drug interactions • Difficult to predict • Changes over the first 2 week period • Drugs can induce themselves and thus counter the inhibitory effects of induction itself • Drug interaction studies necessary • Ritonavir, lopinavir

  9. Other Mechanisms • P-glycoprotein • Transmembrane ATP-dependent, efflux membrane transport protein that is widely distributed in the GI tract, liver, and kidney • Absorption of the drugs, such as the proteaseinhibitors, may be decreased, leading to variations in bioavailability • Inhibition of p-glycoprotein may increase penetration/absorption • Inhibited by ritonavir and probenecid • Multidrug resistance proteins 1 and 2 • Inhibition of these proteins increases penetration of protease inhibitors into CNS, seminal fluid, etc.

  10. Boosted Saquinavir • First boosted regimen employed: saquinavir hard gel caps (Invirase) 400 mg + ritonavir 400 mg bid with food • Higher levels of saquinavir than could be achieved • Increased toxicity: GI upset, hepatitis, hyperlipidemia, fat redistribution • Soft gel caps (Fortovase) better absorbed but more GI upset

  11. Boosted Saquinavir • Saquinavir hard gel caps (Invirase) • Twice a day: SQV 5 x 200 mg + RTV 100 mg, both bid taken together, optimally with food • Once a day: SQV 8x200 mg + RTV 100-200 mg, both once a day, optimally with food • Less GI upset, hepatitis, hyperlipidemia • Decreases meal dependence, dosing frequency and increases levels of SQV • Eliminates need to refrigerate soft gel caps • Can overcome decreased levels due to nevirapine or efavirenz interactions

  12. Boosted Indinavir • Indinavir dosing normally q8hours on an empty stomach • Regimens • Indinavir 2 x 400 mg + ritonavir 100-200 bid with or without food • Indinavir 400 mg + ritonavir 200 mg bid with or without food • Boosting decreases dosing frequency and meal dependence • Overcomes nevirapine or efavirenz problems

  13. Boosted Atazanavir • Atazanavir approved 2003 • Atazanavir levels decreased by tenofovir, efavirenz • Unboosted regimen: atazanavir 2 x 200 mg caps q24h • Boosted Regimen: atazanavir 2 x 150-200 mg once a day with food + 100 mg ritonavir once a day • Boosting increases incidence of hyperlipidemia and possibly of jaundice • Studies suggest that boosted atazanavir may be a useful salvage strategy similar to lopinavir/ritonavir

  14. Boosted Fosamprenavir • Unboosted fosamprenavir 2 x 700 mg bid • Boosted regimens: • Fosamprenavir 1 x 700 mg + ritonavir 100 mg, both bid • Fosamprenavir 2 x 700 mg + ritonavir 2 x 100 mg, both once a day – recommended for naïve patients only • Probably best used as first line boosted PI • May be able to overcome some PI resistance • Well tolerated • Increased hyperlipidemia with boosted regimen • May overcome nevirapine and efavirenz interactions

  15. PI – NNRTI Interactions ↓ • Nevirapine: a P-450 inducer • Decreases lopinavir/ritonavir levels (27% AUC, 50% dec Cmin) • Decreases indinavir levels (28% dec AUC) • Decreases fosamprenavir levels (33% dec AUC) • Decreases nelfinavir levels (32% dec Cmin) • Decreases saquinavir levels (27% dec AUC) • Unknown: atazanavir • Compensate for P-450 induction • Increase dosage or boost: indinavir, lopinavir/ritonavir • Increase nelfinavir • Boost fosamprenavir, saquinavir

  16. Nevirapine Effect on PIs

  17. PI – NNRTI Interactions • Efavirenz: a P-450 inducer/inhibitor • Decreases lopinavir/ritonavir levels (19% dec AUC, 39% dec Cmin) • Decreases indinavir levels (31% AUC, 16% dec Cmax) • Decreases fosamprenavir levels (36% dec AUC) • No significant nelfinavir interaction (20% inc AUC, 37% dec in AUC metabolite) • Decreases saquinavir levels (62% dec AUC, 50 dec Cmax) • Decreases atazanavir levels (21% dec AUC) • Compensate for P-450 induction/inhibition • Increase dosage or boost: indinavir, lopinavir/ritonavir • No change in nelfinavir • Boost fosamprenavir, saquinavir?, atazanavir

  18. Efavirenz Effect on PIs

  19. Tenofovir Interactions • Nucleotide antiretroviral • Atazanavir • Decreases atazanavir levels • Levels of tenofovir increased by atazanavir • Compensate by using boosted atazanavir and observe for tenofovir toxicity • Lopinavir/ritonavir • Levels of tenofovir increased: observe for toxicity • Didanosine • Levels of didanosine increased (144-160% AUC) • Compensate by decreasing dose of didanosine

  20. PI-PI interactionsLopinavir - fosamprenavir/amprenavir • Poorly tolerated • Slightly decreased lopinavir and moderately decreased amprenavir levels • Adding extra ritonavir further reduces amprenavir!!!

  21. PI-PI Interactionssaquinavir - atazanavir - ritonavir • Normal atazanavir levels • Boosted the trough levels of saquinavir 112% over baseline, peak levels by 42%, area under the curve by 60% and extended the saquinavir half-life by 17% • Atazanavir reduced the trough levels of ritonavir by 28% and the half-life by 17% (this latter result was not statistically significant); but peak levels were boosted by 58% and AUC by 41%.

  22. PI-PI InteractionsLopinavir/ritonavir – saquinavir • Synergistic against viruses resistant to LPV but still sensitive to SQV • Limited data on interactions • Dosing • Standard lopinavir/ritonavir 400/100 bid • Invirase 800-1000 bid

  23. PI-PI InteractionsLopinavir/ritonavir – indinavir • Indinavir (600 mg twice daily) when coadministered with Kaletra (400/100 mg twice daily) may produce a similar AUC and higher Cmin relative to the established clinical dosing regimen • 11 subjects

  24. PI-PI Interactionsindinavir - saquinavir • Coadministration of indinavir (800 mg three times daily) and a single dose of the soft gel formulation of saquinavir (800 or 1200 mg single dose) • N = 6 • 800 mg saquinavir dose showed a 620% increase in AUC and a 551% increase in Cmax. • 1200 mg saquinavir dose showed a 364% increase in AUC and a 299% increase in Cmax. • There were no apparent clinically relevant changes to indinavir pharmacokinetics when coadministered with the soft gel formulation of saquinavir.

  25. Unknown Interactions • Atazanavir - nevirapine • Lopinavir/ritonavir - atazanavir

  26. Adverse PI InteractionsMany Overcome By Boosting • Lopinavir + amprenavir or fosamprenavir • Saquinavir + nevirapine or efavirenz • Atazanavir + tenofovir • Atazanavir + efavirenz • Atazanavir + efavirenz + tenofovir • Atazanavir + nevirapine • Indinavir + nevirapine or efavirenz • Fosamprenavir + nevirapine or efavirenz

  27. Patient 1 • 22 y/o man with AIDS CD4 122 VL > 750k DMAC • 122 lbs • Cr 1.4 • Resistance testing: M184V, 215, 219, 82, 84 • Proposed regimen • Lopinavir/ritonavir • Efavirenz • Tenofovir • Didanosine

  28. Patient 1 • 22 y/o man with AIDS CD4 122 VL > 750k DMAC • 122 lbs, 69 in • Nephropathy Cr 1.9 • Resistance testing: M184V, 215, 219, 82, 84 • Proposed regimen • Lopinavir/ritonavir: levels decreased by efavirenz • Efavirenz • Tenofovir • Didanosine

  29. Patient 1 • 22 y/o man with AIDS CD4 122 VL > 750k DMAC • 122 lbs • Cr 1.4 • Resistance testing: M184V, 215, 219, 82, 84 • Proposed regimen • Lopinavir/ritonavir • Efavirenz • Tenofovir: levels increased by renal failure and lopinavir/rtv • Didanosine

  30. Patient 1 • 22 y/o man with AIDS CD4 122 VL > 750k DMAC • 122 lbs • Cr 1.6 • Resistance testing: M184V, 215, 219, 82, 84 • Proposed regimen • Lopinavir/ritonavir • Efavirenz • Tenofovir • Didanosine: levels increased by low weight, renal failure, and tenofovir

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  37. Final Recommendations • Look up all interactions using a computer or PDA • Avoid using drugs together which have not been studied • Pay close attention to body weight, hepatic and renal impairment • Follow liver enzymes and renal function closely

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