Pharmacokinetics of indinavir and ritonavir administered at 667 and 100 milligrams, respectively, every 12 hours compared with indinavir administered at 800 milligrams every 8 hours in human immunodeficiency virus-infected patients.

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 (Cmin) and area under the concentration-time 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 Cmin and AUC at 24 h (AUC24) 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/RTV at 400/400 mg provided suppression of HIV RNA to undetectable levels (<80 copies/ml) in 59.5% of HIV-infected antiretroviral-naive individuals, but patients presented with side effects characteristic of RTV, as well as IDV (17). Pharmacokinetic and clinical data with IDV/RTV at 400/100 mg appear comparable to those seen with the IDV 800-mg q8h regimen, but no direct comparison has been performed (5, 6, 12, 15). There are no pharmacokinetic studies that directly compare a regimen of IDV/RTV q12h, which includes an IDV dose of <800 mg and low-dose RTV (100 mg), directly with the standard IDV 800-mg q8h regimen. In the present study, pharmacokinetic parameters (Cmin, Cmax, and AUC from 0 to 24 h [AUC0-24]) of a lower-dose regimen consisting of IDV/RTV at 667/100 mg q12h were compared to those of the standard IDV 800-mg q8h regimen. The 667-mg IDV q12h regimen offers greater convenience and potentially better adherence than the IDV 800-mg q8h regimen due to less-frequent dosing. The primary objective was to compare the Cmin of the IDV/RTV 667/100-mg regimen to that of the IDV 800-mg q8h regimen, as well as fully characterize the pharmacokinetics of the lower-dose regimen. The tolerability of both regimens was also evaluated as a secondary study endpoint.