Competing drug-drug interactions among multidrug antiretroviral regimens used in the treatment of HIV-infected subjects: ACTG 884

Objective: To evaluate the steady state concentrations of saquinavir, riton avir, nelfinavir, delavirdine, and adefovir in six different three- and fou r-drug combination regimens. Design: Randomized, partially double-blinded, multicenter study in a popula tion of indinavir-experienced subjects with virologic failure. The first se ven subjects enrolled in each of the six treatment arms from 10 participati ng sites were entered into this pharmacokinetic evaluation. Setting: Multicenter study of the AIDS Clinical Trials Group (ACTG). Patients: HIV-infected subjects. Interventions: A 12-hour pharmacokinetic study was conducted after 2 weeks of drug administration. Main outcome measures: Area under the concentration-time curve with statist ical comparisons to evaluate the effect of the second protease inhibitor an d the effect of the non-protease inhibitors. Results: There was no difference in saquinavir concentrations according to whether the second protease inhibitor was ritonavir or nelfinavir. Saquinav ir concentrations in the groups receiving the combination of delavirdine pl us adefovir dipivoxil were reduced by approximately 50% compared with those receiving delavirdine. Delavirdine concentrations were reduced by approxim ately 50%, in the delavirdine plus adefovir dipivoxil arms compared with th e delavirdine arms. Conclusions: Saquinavir concentrations were significantly lower in the arms containing the combination of delavirdine and adefovir dipivoxil compared with the arms containing delavirdine. Delavirdine concentrations were signi ficantly lower when coadministered with adefovir dipivoxil. These drug-drug interactions were not expected, the mechanism(s) is (are) not clear, and a dditional studies are warranted. This study illustrates the need to underst and more fully the pharmacokinetic characteristics of complex combination a ntiretroviral regimens prior to use in patient management. (C) 2000 Lippinc ott Williams & Wilkins.