PHARMACOKINETIC STUDY OF THE INTERACTION BETWEEN RIFABUTIN AND DELAVIRDINE MESYLATE IN HIV-1-INFECTED PATIENTS

The oxidative metabolism of delavirdine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is mediated in part by cytochrome P450 3 A. The influence of rifabutin, an inducer of certain human cylochrome P450 isozymes, on the steady-state pharmacokinetics of delavirdine was investigated in 12 HIV-positive patients with CD4 counts ranging from 75 to 671/mm(3) Both the control group (n = 5) and the rifabutin grou p (n = 7) received 400 mg delavirdine mesylate every 8 h for 30 days, subjects in the rifabutin group took a 300 mg, once-daily dose of rifa butin on study days 16-30. Harvested plasma from serial blood samples collected after dosing on days 15, 16, and 30 was assayed for delavird ine and its N-desalkyl metabolite concentrations using a reversed-phas e HPLC method. Blood samples obtained on days 16 and 30 were also assa yed for rifabutin by HPLC. Delavirdine mesylate alone or in combinatio n with rifabutin was well-tolerated. On day 30, statistically signific ant differences between groups were observed for all delavirdine pharm acokinetic parameters (P < 0.046). After coadministration of rifabutin and delavirdine mesylate for 2 weeks, oral clearance of delavirdine i ncreased five-fold, resulting in lower steady-state plasma delavirdine concentrations. Rifabutin pharmacokinetic parameters were similar to those previously reported. Concomitant use of delavirdine and rifabuti n al the recommended dose for each drug is discouraged. Maintaining th erapeutic concentrations of delavirdine in patients on both medication s may require dose modification. (C) 1997 Elsevier Science B.V.