The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin*

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Abstract
To investigate the effects of ritonavir on the pharmacokinetics of rifabutin.In a multiple-dose, randomized, parallel-group, double-blind study, subjects received 150 mg rifabutin daily for 24 days coadministered on days 15 to 24 with twice-daily doses of either placebo or ritonavir (300 mg on day 15, 400 mg on day 16, and 500 mg on days 17 to 24). Plasma concentrations of rifabutin and 25-O-desacetylrifabutin were measured by HPLC, and the pharmacokinetics were determined after the rifabutin doses on days 14 and 24.For subjects receiving rifabutin and placebo who completed the study (n = 11), there were small but statistically significant differences (< or = 32%) in several rifabutin and 25-O-desacetylrifabutin pharmacokinetic parameters between the regimens of rifabutin alone and rifabutin with placebo. In contrast, the effect of ritonavir on rifabutin pharmacokinetics of subjects completing the study (n = 5) was substantial. Rifabutin mean minimum observed concentration (Cmin), maximum observed concentration (Cmax), and area under the concentration-time curve [AUC(0-24)] increased by approximately sixfold, 2.5-fold, and fourfold, respectively, and 25-O-desacetylrifabutin mean Cmin, Cmax, and AUC(0-24) increased by approximately 200-, 16-, and 35-fold, respectively, when coadministered with ritonavir compared with rifabutin administered alone. The sum of the mean AUC(0-24) of rifabutin and 25-O-desacetylrifabutin increased nearly sevenfold when coadministered with ritonavir.Ritonavir inhibited the metabolism of rifabutin and 25-O-desacetylrifabutin, suggesting that both are metabolized at least in part by CYP3A. Ritonavir may have enhanced rifabutin bioavailability by reducing either intestinal of hepatic metabolism of both. Clarithromycin is an alternative to rifabutin for antimycobacterial therapy that may be administered concurrently with ritonavir. Administration of ritonavir with a reduced rifabutin dosage regimen (150 mg every Monday, Wednesday, and Friday) is being investigated.