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Session 28 Oral Abstract Session Pharmacology of Antiretroviral Chemotherapeutic Agents: Pharmacokinetics and Therapeutic Drug Monitoring Session Time: Wednesday, 11:15 am - 12:30 pm Room 6E

12:00   129. The Inhibitory Quotient (IQ) for Saquinavir (SQV) Predicts Virologic Response to Salvage Therapy C. V. Fletcher*1, H. Cheng2, S. A. Fiscus3, R. Swanstrom3, N. S. Hellmann4, R. Haubrich5, D. Katzenstein6, and R. Gulick7 for the ACTG 359 Team 1Univ. of Minnesota, Minneapolis; 2Harvard Sch. of Publ. Hlth., Boston, MA; 3Univ. of North Carolina, Chapel Hill; 4ViroLogic Inc., South San Francisco, CA; 5Univ. of California, San Diego; 6Stanford Univ. Med. Ctr., Palo Alto, CA; and 7Weill Med. Coll. of Cornell Univ., New York, NY Background: ACTG 359 was a controlled study of SQV (soft gel) with ritonavir (RTV) or nelfinavir (NFV), and delavirdine (DLV), adefovir (ADV), or both. In this report, relationships between SQV IQ and virologic response were investigated in a pharmacology substudy. Methods: SQV was dosed at 400 mg with 400 mg RTV q12h or 800 mg with 750 mg of NFV q8h. SQV pharmacokinetic characteristics were measured trough (either 8-hour or 12-hour post dose), and the 24-hour AUC at week 2. Virologic characteristics were baseline phenotypic susceptibility (IC50, PhenoSense) and HIV RNA at weeks 0, 4, 8, 12, and 16. SQV trough-IQ was calculated as trough/IC50, and AUC-IQ as AUC/IC50 without protein binding adjustment. Spearman correlation was used to examine bivariate relationships between IQ and HIV RNA response. Linear regression on log-transformed IQ was used to adjust for other study regimens. All p-values are 2-sided. Results: IQ data were available on 34 subjects. SQV trough-IQ was negatively (higher IQ had lower HIV RNA) correlated with HIV RNA changes from baseline at weeks 4 (r = -0.44, p=0.009); 8 (-0.33, p=0.058); 12 (-0.32, p=0.060); and 16 (-0.16, p=0.378). Median trough-IQ was 17.2 (n=7) for subjects with week 4 HIV RNA above baseline, compared with 207.2 (n=27) for those below. Week 16 values were 138.1 and 178.6, respectively. After adjusting for other study regimens, SQV trough-IQ was strongly associated with week 4 HIV RNA change from baseline (p=0.004), but not at other time points (p>0.144). SQV AUC-IQ had a similar trend. In adjusted analyses, AUC-IQ was associated with week 4 RNA change from baseline (p=0.002) and week 8 (p=0.024). Conclusions: SQV IQ was significantly correlated with early virologic response in both adjusted and unadjusted analyses. The association of a higher IQ with greater reduction in HIV RNA in these preliminary analyses indicates potential strategies to optimize therapeutic response.

©2002 9th Conference on Retroviruses and Opportunistic Infections