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AIDS-related morbidity and mortality have declined sharply with the use of potent antiretroviral regimens. Despite the clinical benefit observed with highly active antiretroviral therapy, inevitably most regimens fail; failure rates of 20 to 50% have been reported within the first year of triple-drug therapy (4, 21, 25). Virologic failure rates increase rapidly with successive therapeutic regimens (19, 24); thus, the management of patients who have failed several previous courses of antiretroviral therapy is a major challenge in clinical practice (9). Since a conventional drug regimen cannot be offered to these patients, multiple-drug rescue therapies have been used. Sometimes these therapies have to include dual human immunodeficiency virus (HIV) protease inhibitor (PI) combinations at therapeutic doses (5). PIs undergo cytochrome P450-based metabolism in the gastrointestinal tract and liver, and they are subject to potentially significant drug-drug interactions. In addition, all PIs are substrates for transport by the P-glycoprotein drug transport protein (18, 27). Such interactions may be beneficial when two PIs are administered simultaneously. For example, ritonavir is a potent inhibitor of some cytochrome P450 isoenzymes and of the P-glycoprotein, and when it is coadministered with other PIs there is a considerable increase in their concentrations in plasma (14, 22). Saquinavir was the first PI available for the treatment of patients with HIV infection. The bioavailability of saquinavir is low, but when it is coadministered with ritonavir, concentrations of saquinavir in plasma increase enormously (28). The first combination of PIs used was saquinavir and ritonavir, each at doses of 400 mg (3). The combination of 1,000 mg of saquinavir and 100 mg of ritonavir, both twice daily (b.i.d.), results in higher exposure to saquinavir than that obtained with a 400-mg-400-mg b.i.d. combination of saquinavir and ritonavir (28, 31). With regard to saquinavir concentration, the boosting effects of different doses of ritonavir ranging from 100 to 400 mg b.i.d. are similar (15), and with the 100-mg dose, the toxic effects of higher doses are minimized (11). Lopinavir was the first commercially marketed PI coformulated with ritonavir to achieve good bioavailability. The usual regimen is 100 mg of ritonavir and 400 mg of lopinavir b.i.d. (6). This fixed combination of lopinavir and low-dose ritonavir (Kaletra) facilitates the simultaneous boosting of another PI. The administration of two PIs boosted with low doses of ritonavir can produce complex drug interactions with unexpected results. A decrease in the concentration of both PIs has been described when lopinavir-ritonavir is administered with amprenavir (6). This unfavorable reaction does not seem to occur when lopinavir-ritonavir is administered with saquinavir (6, 28), but there is little pharmacokinetic data to support the use of this combination. This study reports the steady-state pharmacokinetics of lopinavir, saquinavir and ritonavir administered as a dual-boosted PI combination in HIV-infected adults with multiple prior therapeutic failures and investigates whether the steady-state serum pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. (This work was presented in part at the XIV International AIDS Conference, Barcelona, Spain, 2002 [abstract TuPeB4545].)