Indinavir and Rifabutin Drug Interactions in Healthy Volunteers

Abstract

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three‐period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo to the other drug) or in combination to 10 volunteers for 10 days. In study 2, 150 mg qd of rifabutin together with 800 mg q8h of indinavir, 300 mg qd of rifabutin alone, or 800 mg q8h of indinavir alone was administered to 14 volunteers for 10 days. In study 1, the geometric mean ratio (GMR) (90% confidence interval [CI]) of the AUC(0–8h) of indinavir, coadministered with rifabutin 300 mg qd compared to indinavir alone (with rifabutin placebo), was 0.66 (0.56, 0.77), while that of the AUC(0–24h) of rifabutin, coadministered with indinavir compared to rifabutin alone (with indinavir placebo), was 2.73 (1.99, 3.77). In study 2, the GMR (90% CI) of the AUC(0–8h) of indinavir, coadministered with rifabutin 150 mg qd compared to indinavir alone, was 0.68 (0.60, 0.76), while that of the AUC(0–24h) of rifabutin, when rifabutin 150 mg qd was coadministered with indinavir compared to rifabutin 300 mg qd alone, was 1.54 (1.33, 1.79). For both studies 1 and 2, indinavir and rifabutin administered alone or in combination were generally well tolerated. No clinical or laboratory adverse experience was serious. These data demonstrate the important pharmacokinetic interactions between indinavir and rifabutin when they are coadministered. Indeed, these observations formed the basis for the subsequent ACTG 365 study that explored dose adjustments for these agents in combination regimens to preserve the sustained antiviral activity of indinavir in the absence of adverse events as a result of elevated circulating levels of rifabutin.

Pharmacokinetic Interaction between Fosamprenavir-Ritonavir and Rifabutin in Healthy Subjects

“…2). An absolute neutrophil count Ͻ1,000/mm 3 was observed for one subject receiving RFB with FPV-RTV (800/mm 3 , from a predose baseline of 3,100/mm 3 ), which resolved when the subject was off the study medication. Five ALT elevations were reported as AEs for the combination of RFB and FPV-RTV (Table 4).…”

Pharmacokinetics of Darunavir/Ritonavir and Rifabutin Coadministered in HIV-Negative Healthy Volunteers

“…As this was an explorative, crossover trial, no formal sample size calculations were performed. However, a minimum of at least 13 volunteers completing all sessions was considered sufficient to allow for relevant conclusions (5,12,17,20,22). With this number of volunteers and the expected within-subject variation on the logarithmic scale of 0.035 in AUC from time point zero up to the time point of the last quantifiable concentration (AUC last ) for DRV, the range of the 90% confidence interval (CI) of the ratio was estimated to be from Ϫ12.3% to ϩ14.0%.…”

Effect of Rifampin and Rifabutin on the Pharmacokinetics of Lersivirine and Effect of Lersivirine on the Pharmacokinetics of Rifabutin and 25-O-Desacetyl-Rifabutin in Healthy Subjects

“…Rifabutin is metabolized and eliminated mainly by the CYP3A pathway and is a moderate inducer of CYP3A4 activity (3,18). Rifabutin has an apparent terminal half-life of 45 h (range, 16 to 69 h) (32).…”