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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) Review what is not known Final recommendations 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 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) 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 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 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 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 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 protease inhibitors, 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. P-450 inhibition Increase PI Levels Decrease PI Levels P-450 induction X X P-gly inhibition HRP 1+2 inhibition X X ritonavir indinavir saquinavir P450 inhibition P450 induction P-gly inhibition HRP 1+2 inhibition X X X X X X nelfinavir lopinavir amprenavir X X nevirapine efavirenz X X X X X 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 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 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 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 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 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 ↓ Nevirapine Effect on PIs PI Cmin Increase Dose? Boosting Effective? Yes Yes AUC Cmax lopinavir with ritonavir 73% 50% indinavir 72% Yes Yes fosamprenavir 67% No Yes nelfinavir 68% Yes No saquinavir 73% No Yes atazanavir ? ? Theoretical 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 Efavirenz Effect on PIs Cmax Cmin Increase Dose? Boosting Effective? 61% Yes Yes Yes Yes No Yes PI AUC lopinavir / ritonavir 81% indinavir 69% fosamprenavir 64% nelfinavir / nelfinavir metabolite 120%/ 63% 121%/ 60% No Need No Need saquinavir 38% 50% No ? atazanavir 79% No Yes 84% Tenofovir Interactions Nucleotide antiretroviral Atazanavir Lopinavir/ritonavir Decreases atazanavir levels Levels of tenofovir increased by atazanavir Compensate by using boosted atazanavir and observe for tenofovir toxicity Levels of tenofovir increased: observe for toxicity Didanosine Levels of didanosine increased (144-160% AUC) Compensate by decreasing dose of didanosine PI-PI interactions Lopinavir - fosamprenavir/amprenavir Poorly tolerated Slightly decreased lopinavir and moderately decreased amprenavir levels Adding extra ritonavir further reduces amprenavir!!! PI-PI Interactions saquinavir - 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 halflife 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%. PI-PI Interactions Lopinavir/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 PI-PI Interactions Lopinavir/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 PI-PI Interactions indinavir - 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. Unknown Interactions Atazanavir - nevirapine Lopinavir/ritonavir - atazanavir Adverse PI Interactions Many 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 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 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 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 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 Patient 1 Considerations Drug lopinavir/ritonavir tenofovir efavirenz didanosine Dosage Patient 1 Considerations Low weight Renal failure [Ccr= 48 cc/min] Drug interactions Drug Dosage lopinavir/ritonavir tenofovir efavirenz didanosine Patient 1 Considerations Low weight Renal failure [Ccr= 48 cc/min] Drug interactions Drug Dosage lopinavir/ritonavir 4 caps bid tenofovir efavirenz didanosine Patient 1 Considerations Low weight Renal failure [Ccr= 48 cc/min] Drug interactions Drug Dosage lopinavir/ritonavir 4 caps bid tenofovir 300 mg every 48 hours* efavirenz didanosine Patient 1 Considerations Low weight Renal failure [Ccr= 48 cc/min] Drug interactions Drug Dosage lopinavir/ritonavir 4 caps bid tenofovir 300 mg every 48 hours* efavirenz 600 mg daily didanosine Patient 1 Considerations Low weight Renal failure [Ccr= 48 cc/min] Drug interactions Drug Dosage lopinavir/ritonavir 4 caps bid tenofovir 300 mg every 48 hours* efavirenz 600 mg daily didanosine 100 – 125 mg daily? 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