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Session 102 Poster Session Effect of Gender/Sex on Viral Load, Pharmacokinetics and Responses to Antiretroviral Therapy Session Time: 4:30-6:30 pm Room 4E-F

779-W. Quantitation of Sex Differences and Drug Interactions: Pharmacologic Studies of Saquinavir (SQV) in ACTG 359 R. C. Brundage1, E. Acosta2, R. Haubrich3, D. Katzenstein4, R. Gulick5, and C. V. Fletcher*1 1Univ. of Minnesota, Minneapolis; 2Univ. of Alabama, Birmingham; 3Univ. of California, San Diego; 4Stanford Univ. Med. Ctr., Palo Alto, CA; and 5Weill Med. Coll. of Cornell Univ., New York, NY Background: ACTG 359 was a controlled study of SQV (soft gel) in combination with ritonavir (RTV) or nelfinavir (NFV) together with delavirdine (DLV), adefovir (ADV), or both. A pharmacology substudy obtained 12-hour AUCs in 42 subjects. This substudy found significantly lower SQV and DLV AUCs in subjects taking ADV; furthermore, lower SQV AUCs were associated with higher body weight, higher baseline HIV RNA, and male sex. This report describes a population pharmacokinetic analysis of all subjects in ACTG 359. Methods: SQV was dosed at 400 mg q12h with 400 mg RTV or 800 mg q8h with 750 mg NFV. Concentrations were determined at weeks 4, 8, and 16; on 1 occasion, 2 concentrations were obtained at least 1 hour apart. The final data set consisted of 1022 SQV concentrations from 186 subjects. A 1-compartment first order absorption model was fit to the data (NONMEM). Parameters of interest were clearance (CL) and relative bioavailability (F). Covariates tested for effect were weight, sex, concurrent therapy with RTV, NFV, ADV, or DLV, and baseline HIV-RNA and CD4 cell count. Results: In the RTV arms, SQV CL was 63.3% of the CL in the NFV arms, and F was 90% greater. The SQV half-life was 4.5 hours with RTV vs 2.8 hours with NFV. CL in females was 46.7% of the CL in males. Weight was positively correlated with SQV CL. SQV CL was 49% faster in those arms containing ADV. No significant effect on SQV CL or F was noted for HIV-RNA, CD4 cells, or presence/absence of DLV in the regimen. Conclusions: RTV produced a greater decrease in SQV CL than NFV. Interestingly, F was also greater in the RTV arms. These findings suggest differential inhibitory mechanisms of RTV vs. NFV on SQV CL and F. Overall, RTV caused a 3-fold increase in SQV exposure compared with NFV. ADV significantly decreased SQV half-life to 1.9 hours. SQV CL in females was reduced approximately 50%, increasing AUC approximately 50% and prolonging half-life to 6.1 hours. These findings confirm the significant influence of sex and body weight on SQV and the adverse drug interaction with ADV.

©2002 9th Conference on Retroviruses and Opportunistic Infections