614 3-Way Pharmacokinetic Interaction among Amprenavir, Efavirenz, and a Second Protease Inhibitor G D Morse*1, S Rosenkranz2, M F Para3, E Adams4, K E Yarasheski5, R C Reichman6, and Adult AIDS Clinical Trials Group (AACTG); DAIDS, NIAID, NIH; Bethesda, MD, USA 1State Univ. of New York at Buffalo, USA; 2Harvard Sch. of Publ. Hlth., Boston, MA, USA; 3Ohio State Univ., Columbus USA; 4DAIDS, NIAID, NIH, DHHS, Bethesda, MD, USA; 5Washington Univ., St. Louis, MO, USA; and 6Univ. of Rochester, NY, USA
Background: Drug interaction studies of PI and NNRTI are often based on pre-clinical cytochrome P450 isoform metabolism data. AACTG protocol 5043 was conducted to examine the 2-way pharmacokinetic interaction between amprenavir (APV) and efavirenz (EFV), and the 3-way interactions among APV, EFV, and a second PI (nelfinavir [NFV], indinavir [IDV], ritonavir [RTV] or saquinavir [SQV]) based on anticipated mixed inductive and inhibitory effects.
Methods: Healthy subjects (n = 85) underwent an intensive pharmacokinetic study after a single dose of APV (Day 0). Subjects then received only EFV 600 mg every 24 hours x 10 days, then restarted APV with EFV for days 11 to 13 with a pharmacokinetic study on day 14. A second PI (NFV [1250 mg everu 12 hours], IDV [1200 mg every 12 hours], RTV [100 mg every 12 hours], or SQVsgc [1600 mg every 12 hours]) was added to APV and EFV on day 15 with a repeat pharmacokinetics on day 21. A control group continued APV and EFV without a second PI. APV AUCs were compared, within-subject, between days 21 (with EFV and second PI) and 14 (with EFV only) using the Wilcoxon signed rank test. Confidence intervals (90% CI) around the geometric mean ratios (day 21:day 14) were calculated.
Results: In the 5 arms, APV AUC were 38% to 55% lower (median percent change in AUC) with the addition of EFV (day 14 compared with day 0, all p values <0.05). In the groups receiving NFV, IDV, and RTV, APV AUC with EFV+PI were significantly higher than those with EFV alone; 90% CI around geometric mean ratios were: 3.7 to 5.2 for NFV (p = 0.0001), 3.0 to 5.1 for IDV (p = 0.0001), and 8.3 to 19.3 for RTV (p = 0.0020). The addition of SQV resulted in modest increase in APV AUC (geometric mean ratios 1.1 to 1.5, p = 0.0273). AUC in the control group did not differ significantly from day 14 to 21.
Conclusions: These observations indicate that EFV induction lowers APV AUC. The addition of NFV, IDV, or RTV countered this induction and increased APV AUC significantly after 1 week of triple drug administration. The addition of SQV resulted in a modestly increased AUC. Interestingly, NFV and IDV increased the APV AUC in the presence of EFV in a manner not predicted from prior isoform and 2-way clinical interaction studies. Additional EFV pharmacokinetic analyses are underway.
Keywords: Amprenavir; Efavirenz; Drug Interactions
