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Objective To evaluate the steady state concentrations of saquinavir, ritonavir, nelfinavir, delavirdine, and adefovir in six different three- and four-drug combination regimens. Design Randomized, partially double-blinded, multicenter study in a population of indinavir-experienced subjects with virologic failure. The first seven subjects enrolled in each of the six treatment arms from 10 participating 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 statistical comparisons to evaluate the effect of the second protease inhibitor and 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. Saquinavir concentrations in the groups receiving the combination of delavirdine plus adefovir dipivoxil were reduced by approximately 50% compared with those receiving delavirdine. Delavirdine concentrations were reduced by approximately 50%, in the delavirdine plus adefovir dipivoxil arms compared with the 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 significantly lower when coadministered with adefovir dipivoxil. These drug-drug interactions were not expected, the mechanism(s) is (are) not clear, and additional studies are warranted. This study illustrates the need to understand more fully the pharmacokinetic characteristics of complex combination antiretroviral regimens prior to use in patient management.