A randomized, double-blind, multicenter study of indinavir, zidovudine, and lamivudine was conducted in 320 adults with human immunodeficiency virus type 1 (HIV-1) infection,

Merck & Co, Inc.

max ]) were expressed as geometric mean values with 90% confidence intervals (CI). The primary hypothesis was that the lower bound of the protocol-specified 90% CI for the geometric mean C min ratio of the combination compared to IDV alone regimen would be >2. Twenty-seven patients were enrolled, and 24 (15 male; average age, 42 years) completed the study. The C min , AUC 0-24 , and C max for IDV/RTV compared to IDV alone were 1,511 versus 250 nM, 119,557 versus 77,034 nM ⅐ h, and 10,428 versus 10,407 nM, respectively. Corresponding relationships for IDV/RTV compared to IDV alone were a 6.0-fold increase in C min (90% CI, 4.0, 9.3), an increase in AUC 0-24 (1.5-fold, 90% CI, 1.2, 2.0), and no increase in C max . Adverse events were similar and generally mild, with no cases of nephrolithiasis. The geometric mean ratio of IDV C min for IDV/RTV compared to IDV was at least 2 by a lower bound of the 90% CI, satisfying the primary hypothesis. The C max was not increased, suggesting an IDV/RTV 667/100-mg toxicity profile may be similar to that of unboosted IDV.Single-protease inhibitor regimens significantly reduced the morbidity and mortality associated with human immunodeficiency virus (HIV) following their introduction (19,20). More recently, boosted protease inhibitor regimens combined ritonavir (RTV) with a second protease inhibitor to achieve higher sustained levels of the second protease inhibitor than seen when it was given as part of a single-protease inhibitor regimen. The boosted protease inhibitor regimens may be more effective in suppressing HIV strains with resistance to antiretroviral therapy, including resistance to the second protease inhibitor (2,9,10,18,22,32). In addition, boosted protease inhibitor regimens may be administered less frequently and without regard to meals, potentially improving patient adherence (2, 9, 10, 18, 22, 32). RTV's inhibition of the cytochrome P-450 CYP3A4 enzyme, the primary enzyme in the metabolism of most protease inhibitors, changes the pharmacokinetics of the second protease inhibitor, with elevations of minimum drug concentration (C min ) and area under the concentrationtime curve (AUC) contributing to improved clinical efficacy (2, 10). In addition, RTV's inhibition of P-glycoprotein transport proteins may also contribute to increased concentration of a concomitantly administered protease inhibitor in plasma (33).Indinavir (IDV) is approved for administration every 8 h (q8h) at 800 mg without food (28). Combinations of IDV at 400 to 800 mg and RTV at 100 to 400 mg twice a day (b.i.d.) demonstrated at least equivalent to (and in many cases much higher than) the C min and AUC at 24 h (AUC 24 ) of IDV at 800 mg q8h in normal volunteers and can be administered with food (25). The trough levels maintained with the b.i.d. combinations were above the concentration necessary to inhibit 95% of viral growth of wild-type HIV-1 seen in the absence of drug (8). The most-studied boosted IDV regimen is IDV at 800 mg plus RTV at 100 mg q12h (4,7,21,31). A combination regimen of IDV...