Effect of co-administration of nelfinavir and covariates on the pharmacokinetics of indinavir in ACTG 388 trial

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Pharmacokinetic (PK) interactions among HIV protease inhibitors are expected, as most are substrates for, and inhibitors of, CYP3A4. The goal of this PK analysis was to explore mechanisms for the differences observed in indinavir (IDV) PK among treatment arms (IDV alone, ARM1 or with nelfinavir (NFV), ARM3) in clinical trial ACTG 388 in which HIV-positive patients received IDV 800 mg TID or 1000–1200 mg BID with NFV as part of a multi-drug regimen including lamivudine and zidovudine. Two hundred thirty-four patients provided a total of 727 IDV concentration measurements. These were drawn at week 2 (12 (8) h PK study for ARM3 (1), approximately 10 (8) samples/study; 18 patients) and at week 40 (12h PK study for arm 3, approximately 10 samples/study; 7 patients). An additional random (“population”) sample was drawn at one or more follow-up visits (non-observed prior dose) in 230 patients. A two-compartment PK disposition model with first order absorption and “well stirred” hepatic elimination was fit to the concentration data. The oral clearance (CL/F) of IDV was 49.2 L/h. IDV CL/F was significantly reduced with co-administration of NFV (-26%). Patient weight was associated with a marginal increase of IDV CL/F (5% higher CL/F/10 Kg; p<0.05). Neither gender, age, race, nor height were correlated with IDV CL/F. In conclusion, these data extend our original observation from a small intensive PK substudy and confirm that IDV CL/F was lower when combined with NFV. Clinical Pharmacology & Therapeutics (2004) 75, P82–P82; doi: 10.1016/j.clpt.2003.11.315