Pharmacokinetics of indinavir and ritonavir administered at 667 and 100 milligrams, respectively, every 12 hours compared with indinavir administered at 800 milligrams every 8 hours in human immunodeficiency virus-infected patients.

Human immunodeficiency virus (HIV) patients on nucleoside or nucleotide reverse transcriptase inhibitors with HIV RNA at <1,000 copies/ml were randomized in an open-label study to administration of combined indinavir/ritonavir (IDV/RTV) at 667/100 mg every 12 h (q12h) or IDV alone at 800 mg q8h to determine the regimens' pharmacokinetics. On day 14, plasma IDV and RTV levels were determined over 24 h. Noncompartmental pharmacokinetics (minimum concentration of drug in serum [C(min)], area under the concentration-time curve from 0 to 24 h [AUC(0-24)], and maximum concentration of drug in serum [C(max)]) were expressed as geometric mean values with 90% confidence intervals (CI). The primary hypothesis was that the lower bound of the protocol-specified 90% CI for the geometric mean C(min) ratio of the combination compared to IDV alone regimen would be >/=2. Twenty-seven patients were enrolled, and 24 (15 male; average age, 42 years) completed the study. The C(min), AUC(0-24), and C(max) for IDV/RTV compared to IDV alone were 1,511 versus 250 nM, 119,557 versus 77,034 nM . h, and 10,428 versus 10,407 nM, respectively. Corresponding relationships for IDV/RTV compared to IDV alone were a 6.0-fold increase in C(min) (90% CI, 4.0, 9.3), an increase in AUC(0-24) (1.5-fold, 90% CI, 1.2, 2.0), and no increase in C(max). Adverse events were similar and generally mild, with no cases of nephrolithiasis. The geometric mean ratio of IDV C(min) for IDV/RTV compared to IDV was at least 2 by a lower bound of the 90% CI, satisfying the primary hypothesis. The C(max) was not increased, suggesting an IDV/RTV 667/100-mg toxicity profile may be similar to that of unboosted IDV.

Open-label study of a twice-daily indinavir 800-mg/ritonavir 200-mg regimen in HIV-infected adults failing a protease inhibitor regimen.

There is no standard treatment of HIV-infected patients who fail protease inhibitor (PI)-containing antiretroviral therapy. This open-label, noncomparative 24-week study with a 24-week extension evaluated the efficacy, safety, and tolerability of twice-daily indinavir/ritonavir 800/200 mg plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) in this population. Presented here are the results of the 24-week study. Patients were HIV-infected adults who had prior viral RNA (vRNA) suppression (<400 copies/mL), subsequent failure (> or =400 and < or =100,000 copies/mL) on antiretroviral therapy, and at least one new NRTI available for treatment. The proportions of patients achieving plasma vRNA <400 and <50 copies/mL were analyzed with data as observed (DAO) and intention-to-treat (ITT) models using generalized estimating equations (GEE) or counting noncompleters as failures (NC = F). Mean changes from baseline in vRNA and CD4 cell count were evaluated using DAO and an ITT mixed-model approach. Sixty-three patients (87% male) with a mean age of 42 years and mean baseline vRNA and CD4 cell counts of 3.8 log(10) copies/mL and 360 cells/mm(3), respectively, were enrolled. The proportion (95% confidence interval) of patients achieving vRNA <400 and <50 copies/mL at week 24 were 76% (61%, 87%) and 50% (35%, 65%) for DAO, 64% (50%, 75%) and 43% (30%, 56%) for GEE, and 56% (43%, 68%) and 37% (25%, 50%) for NC = F, respectively. At Week 24, baseline vRNA decreased by >1.0 log(10) copies/mL and CD4 cell counts increased by approximately 90 cells/mm(3). Three patients (5%) experienced serious drug-related adverse events. Seven patients (11%) discontinued treatment due to clinical or laboratory adverse events. In this study, the enhanced, twice-daily regimen of indinavir/ritonavir 800/200 mg plus 2 NRTIs provided suppression of HIV in many patients who had failed a PI-containing regimen and was generally well tolerated.

Open-label study of a twice-daily indinavir 800-mg/ritonavir 100-mg regimen in protease inhibitor-naive HIV-infected adults.

Low-dose ritonavir can boost plasma levels of indinavir, thereby enhancing its antiretroviral activity despite less frequent dosing. In this open-label, noncomparative, 24-week trial with a 24-week extension phase, HIV-infected protease inhibitor (PI)- and lamivudine-naive adults received indinavir/ritonavir 800 mg/100 mg plus stavudine and lamivudine every 12 hours. The proportions of patients achieving plasma HIV RNA (vRNA) <400 and <50 copies/mL were analyzed with data as observed (DAO) and intention-to-treat models using generalized estimating equations (GEE) or counting noncompleters as failures (NC = F). Eighty-nine patients (80% men) with a median age of 36 years and mean baseline vRNA levels and CD4 counts of 5.01 log(10) copies/mL and 269 cells/mm(3) were enrolled. The proportions (95% confidence interval [CI]) of patients achieving vRNA <400 copies/mL were 93% (84%, 98%), 78% (67%, 86%), and 68% (57%, 78%) at week 24 for DAO, GEE, and NC = F analyses, respectively; the corresponding results at week 48 were 95% (84%, 99%), 65% (53%, 76%), and 45% (35%, 57%). Most patients with vRNA <400 had <50 copies/mL. At week 48, baseline vRNA decreased by >2 log(10) copies/mL and CD4 counts increased by approximately 200 cells/mm(3). Five patients (6%) experienced serious drug-related adverse experiences. Twenty patients (23%) discontinued therapy due to adverse experiences. In this study, twice-daily indinavir 800 mg/ritonavir 100 mg with two nucleoside reverse transcriptase inhibitors provided potent viral suppression and immunologic reconstitution in many PI-naive patients.