Trade name: Crixivan (Merck Research Laboratories)
Form: 100, 200 and 400 mg capsules.
Clinical trials: Phase I/II trials show a dose-dependent antiviral effect; with 600-800 mg tid, the mean decrease in viral burden was 1-1.5 logs in those receiving monotherapy and >2 logs with combination therapy using indinavir plus a nucleoside analog. Indinavir + AZT +ddI in patients with CD4 <500/mm 3 and viral burden > 20,000 copies/ml showed a mean CD4 count increase of 80-90/mm 3 and decrease in viral burden of >2 logs at 24 wks (3rd Annual Retroviral and Opportunistic Infection Meeting, Washington, DC, 2/96, Abstract 200). Similar results were noted with indinavir + AZT + 3TC in patients with CD4 counts of 50-400/mm 3 and median viral burden 40,000 copies/ml; at 26 weeks the mean CD4 count increase was 100/mm 3 and the decrease in viral burden was >2 logs.
Dose: 800 mg po tid in fasting state; always use in combination, usually with a nucleoside analog.
Pharmacology: Bioavailability--Absorption is best with fasting state C max = peak > 200 nM; 8 hrs post dose--8 nM (95% inhibition at 25-100 nM in vitro)
T 1/2 serum--1.5-2 hr.
Excretion--Metabolized, mostly through hepatic glucuronidation and p450 dependent pathways. Urine shows 5012% unchanged metabolites.
- Asymptomatic increase in indirect bilirubin to 2.5 mg/ml without increase in transaminase noted in 10-15% of patients.
- Nephrolithiasis = hematuria in 2-15%. Should take 48 oz fluid daily.
- Less common: increased transminase levels, headache, nausea, vomiting, diarrhea, metallic taste, fatigue, insomnia, blurred vision, dizziness, rash thrombocytopenia.
- Nucleoside analogs (AZT, ddI, ddC, d4T and 3TC): none known.
- Ketoconazole: increases levels of indinavir by 70%.
- Rifampin and rifabutin: decreases level of indinavir and increases levels of rifampin or rifabutin.
Trade name:Norvir (Abbott Laboratories)
Form:100 mg capsules; cost (AWP): 168 caps (2-week supply)--$257.
Clinical trials: Phase I/II trials have shown that ritonavir as a single agent has dose-related antiviral activity with median maximum reduction in viral load of 1.7-1.9 logs at 4-8 weeks and median increases in CD4 counts of 230/mm 3 at 32 weeks (NEJM 1995; 333: 1534; NEJM 1995; 333:1528). A phase III trial of ritonavir plus nucleoside analogs in patients with CD4 counts <100/mm 3 showed a 58% decrease in AIDS-defining events or death in ritonavir recipients compared to those continued on nucleoside analogs alone (3rd Conference on Retroviruses and Opportunistic Infection, Washington, DC, January 28-February 1, 1996, Abstract LB6(a). This is the only protease inhibitor that received "traditional approval," a decision based on the demonstration of a clinical benefit.
Dose: 600 mg po bid
T 1/2 serum: 3-4 hrs
C max: 7-11 mg/ml (2.1 mg/ul = 95% inhibitory concentration)
Elimination: Metabolized to 5 metabolites primarily by cytochrome P450 3A; 11% excreted in urine and 86% in feces.
Side effects: Dose related--GI intolerance (nausea, vomiting, diarrhea, taste perversion and/or abdominal pain in 30-50%) and circumoral or peripheral paresthesias (5%). GI intolerance was sufficiently severe to require discontinuation in 15-25% of participants in initial clinical trials, but the formulation marketed appears to be better tolerated. Cholesterol levels increase 30-40%, and triglyceride levels increase 200-300%. Triglyceride levels>1500 mg/ml were noted in 3-10%. Other side effects are asthenia (15-25%), and elevated transaminase (3-7%).
Drug Interaction: Potent inhibition of cytochrome P450 isoforms will presumably increase levels of multiple drugs metabolized by this mechanism. Ritonavir is expected to produce large increases in the plasma concentrations of the following drugs: amiodarone, astemizole, bepridil, bupropion, cisapride, clozapine, encainide, flecainide, meperidine, piroxicam, propafenone, propoxyphene, quinidine, rifabutin, and terfenadine. These agents have recognized risks of arrhythmias, hematologic abnormalities, seizures, or other potentially serious adverse effects and should not be given with ritonavir. Ritonavir co-administration is also likely to produce large increases in these highly metabolized sedatives and hypnotics: alprazolam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, and zolpidem. Due to the potential for extreme sedation and respiratory depression from these agents, they should not be given with ritonavir. Co-administration increases levels of erythromycin, clarithromycin, fentanyl, oxycodone, coumadin, carbamazepine, tricyclic antidepressants, calcium channel blockers, neuroleptics and oral hyoglycemics. There is a reduction in levels of theophylline, atovaquone and lorazepam. There is also a reduction in levels of estradiol with oral contraceptives so that alternative methods of birth control should be sought.
Trade name: Invirase (Hoffman-LaRoche)
Form and price: 200 mg cap at $1.75/200 mg ($5800/year)
Reimbursement: Hotline and Medical Needs Program 800-282-7780.
Class: Protease inhibitor
Indications (FDA labeling): Indicated for advanced HIV infection in combination with nucleoside analogs
Trials: Three trials have evaluated saquinavir plus ddC and/or AZT in 810 patients:
- Italian dose-ranging study (V-13330) in advanced HIV (mean CD4--179/mm 3) showed saquinavir + AZT was superior to AZT monotherapy with increases in CD4 count if saquinavir dose was 600 mg tid.
- ACTG 229 showed saquinavir (600 mg tid) + AZT + ddC was superior to AZT + ddC in CD4 count response.
- North American study (NV 14256) showed saquinavir + ddC is superior to ddC alone or saquinavir alone in terms of CD4 cell count response.
Note: The minimum effective dose is 1800 mg/day. Studies with saquinavir + AZT or ddC show mean CD4 count increases of 30-50/mm 3 at 16-48 weeks and decreases in viral RNA levels averaging 0.5 log. Monotherapy with saquinavir shows minimal effect on surrogate markers. The FDA has approved saquinavir for use in combination with any approved nucleoside analog, although the only studies that have been done are with saquinavir plus AZT and/or ddC. When saquinavir was added to AZT after prolonged AZT use, there was little evidence of activity by AZT. Studies of viral burden show combination treatment is more effective with mean decreases of 0.5-1.0 log compared to 0.1-0.2 log for saquinavir alone. Higher doses of saquinavir (3600-7200 mg/d) produced greater antiviral effect and CD4 response.
Resistance:Genotypic resistance at L90M (most common, 3-fold decrease in sensitivity) and G48V (less common, 30-fold decrease in sensitivity). There is no established cross-resistance with other protease inhibitors such as invirase and ritonavir. The initial experience with AZT plus saquinavir for 8-12 months suggests delayed resistance to AZT compared to AZT monotherapy.
Dose: 600 mg po tid. (Doses of 3.6 and 7.2 gm/day produce greater activity in terms of CD4 counts response and decreases in viral burden of up to 2 logs: dose of 1800 mg/d was approved by FDA because this was the dose used in phase 3 trials.)
Pharmacology:Bioavailability: absorption is 4% with high-fat diet (1,000 calories with 60 gm fat). Should be taken within 2 hours of fatty meal to increase absorption.
T 1/2: 1-2 hours
Elimination: 96% biliary excretion via cytochrome P450; 1% urine. Dose modification in renal failure or liver failure: no data.
Side effects: GI intolerance with nausea, abdominal pain and diarrhea in 4-6% (dose related); headache.
Drug interactions: Rifampin reduces saquinavir levels by 80%, rifabutin by 40%; other drugs that may reduce saquinavir levels are phenobarbital, phenytoin, dexamethasone, and carbamazepine. Recommendation for MAC prophylaxis is clarithromycin rather than rifabutin. Ketoconazole increases levels of saquinavir 150%; itraconazole and fluconazole presumably incrase levels as well. Saquinavir may increase levels of terfenadine or astemizole (and presumably cisapride) with possible serious arrhythmias. It may also increase levels of calcium channel blockers, clindamycin, dapsone, quinidine and triazolam.
Pregnancy: Class B. Studies in rats showed no teratogenicity or embryotoxicity.