1. Pharmacokinetic Interaction between Ritonavir and Indinavir in Healthy Volunteers
- Author
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John M. Leonard, G. Richard Granneman, Ann Hsu, Guoliang Cao, Jeanne Berg, Eugene Sun, Suzana Dennis, Keith Erdman, Tawakol El-Shourbagy, Anthony J. Japour, and Lori Carothers
- Subjects
Adult ,Male ,Adolescent ,Anti-HIV Agents ,viruses ,Cmax ,Indinavir ,Pharmacology ,Models, Biological ,Drug Administration Schedule ,Cmin ,Pharmacokinetics ,immune system diseases ,medicine ,Humans ,heterocyclic compounds ,Drug Interactions ,Pharmacology (medical) ,Ritonavir ,Dose-Response Relationship, Drug ,business.industry ,virus diseases ,HIV Protease Inhibitors ,biochemical phenomena, metabolism, and nutrition ,Middle Aged ,Infectious Diseases ,Nelfinavir ,Drug Therapy, Combination ,Female ,business ,Saquinavir ,Viral load ,medicine.drug - Abstract
Recent advances in the management of human immunodeficiency virus (HIV) infection have led to a new perception of the disease and new treatment paradigms (10). These advances include an improved understanding of the pathogenesis of HIV infection (20, 52), the development of reliable assay methodologies for the detection and quantification of viral load (48, 49), the availability of new, potent antiviral agents, and an appreciation that combination antiretroviral therapy reduces disease progression and mortality risks (7, 8, 16, 19, 37). In this context, indinavir, ritonavir, saquinavir, and nelfinavir are the promising new HIV protease inhibitors for the treatment of HIV infection. More potent and sustained suppression of viral replication and durable immunoreconstitution has been shown with the use of dual protease inhibitors or protease inhibitors in combination with nucleoside analogs compared with the suppression achieved with monotherapy (9, 13, 15, 37, 42, 43, 54, 55, 57, 60, 62). Despite these encouraging advances, anti-HIV therapy remains suboptimal. The durability of the antiviral effect is transient in some individuals. Furthermore, effective combination therapies often demand complex regimens that may involve burdensome frequent dosing, side effects, food restrictions, and hydration requirements. These factors reduce the level of patient adherence to the treatment regimen and may ultimately lead to treatment failure. Indinavir is a potent HIV protease inhibitor, with an in vitro 90% inhibitory concentration (IC90) (HIV-1IIIB) of approximately 0.1 μg/ml in a system containing 50% human serum and 10% fetal calf serum (1, 46, 47). Indinavir is rapidly metabolized by cytochrome P-450 3A isoenzymes (CYP3A), the major enzymes present in the liver and gastrointestinal tract, with an elimination half-life of 1.8 h (11, 45). The renal clearance (CLR) of indinavir is reported to be relatively constant over a wide range of concentrations (4, 63). When given as an 800-mg regimen three times a day (t.i.d.) under fasting conditions, the mean steady-state area under the concentration-time curve (AUC) of indinavir for HIV-infected patients over one dose interval was reported to be 18.8 μg · h/ml (37% coefficient of variation [CV]), and the maximum concentration of drug in serum (Cmax) and the minimum concentration in serum (Cmin) were reported to be 7.73 μg/ml (32% CV) and 0.154 μg/ml (71% CV), respectively (45). Meals with high fat and protein contents decreased the indinavir AUC and Cmax by 80 and 85%, respectively (45). To maintain therapeutic concentrations in plasma, indinavir is given at high doses on a strict schedule of once every 8 h (q8h) with rigid meal schedules. Ritonavir has relatively high bioavailability and an elimination half-life of 3 to 5 h (1, 25, 27, 38). Although it is about 99% protein bound when it is given at a dosage of 600 mg twice daily (b.i.d.) concentrations in plasma in excess of the protein binding-adjusted IC90 (2.1 μg/ml) are usually maintained throughout the dosing interval (14). The bioavailability of ritonavir is minimally affected by food (1). Ritonavir is a potent CYP3A inhibitor in vitro (34), with an estimated Ki of 0.085 μg/ml for indinavir in experiments with human liver microsomes (33a). In rats, the combined administration of ritonavir and indinavir (10 mg/kg of body weight for each drug) resulted in an eightfold increase in the indinavir AUC compared to that for indinavir given alone (26, 28). Recently, we described a clinically significant interaction between ritonavir and saquinavir (22). Probably due to the inhibition of the CYP3A metabolism of saquinavir by ritonavir, saquinavir AUC values were greatly enhanced (>50-fold) when saquinavir was coadministered with ritonavir; the combination regimen given b.i.d. with reduced doses of both drugs has been shown to suppress the level of viral RNA to below quantitation limits (
- Published
- 1998