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Antimicrobial Agents and Chemotherapy, January 2003, p. 130-137, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.130-137.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics and Pharmacodynamics of Efavirenz, Nelfinavir, and Indinavir: Adult AIDS Clinical Trial Group Study 398

Departments of Laboratory Medicine and Biopharmaceutical Sciences, University of California, San Francisco, San Francisco, California,¹ Division of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York,² Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,³ Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts⁴

Received 24 April 2002/ Returned for modification 8 August 2002/ Accepted 3 October 2002

The present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo. The PK databases consisted of 531 EFV concentrations (139 patients), 219 NFV concentrations (75 patients), and 66 IDV concentrations (11 patients). Time to virological failure was ascertained for all patients in the PK databases. PK data were fit with a population PK model that assumed exclusive hepatic elimination (the well-stirred model). Notable findings with respect to EFV PK and PD are as follows. (i) The hepatic clearance of EFV is unaltered by NFV, IDV, or SQV coadministration. (ii) The hepatic clearance of EFV appears to be 28% higher in white non-Hispanics than in African Americans and Hispanics (P = 0.03). (iii) Higher adherence scores (as measured with the Medication Event Monitoring System) are associated with marginally increased levels of exposure to EFV. (iv) In patients with no prior experience with nonnucleoside reverse transcriptase inhibitors (NNRTIs), a given percent increase in the oral clearance (CL/F) of EFV is associated with a greater percent increase in the hazard of virological failure (P < 0.0003). Among NNRTI-experienced patients, however, hazard is relatively uncorrelated with EFV CL/F.

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