The influence of efavirenz on the pharmacokinetics of a twice-daily combination of indinavir and low-dose ritonavir in healthy Volunteers

• Published in: Clinical pharmacology and therapeutics 2002-01, Vol.71 (1), p.57-67
• Main Authors: Aarnoutse, Rob E., Grintjes, Karin J. T., Telgt, Denise S. C., Stek, Michael, Hugen, Patricia W. H., Reiss, Peter, Koopmans, Peter P., Hekster, Yechiel A., Burger, David M.
• Format: Article
• Language: English
• Subjects: Adult; Anti-HIV Agents - adverse effects; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Area Under Curve; Benzoxazines; Biological and medical sciences; Chromatography, High Pressure Liquid; Drug Interactions; Drug Therapy, Combination; Half-Life; HIV Protease Inhibitors - adverse effects; HIV Protease Inhibitors - pharmacokinetics; Humans; Indinavir - adverse effects; Indinavir - pharmacokinetics; Male; Medical sciences; Middle Aged; Oxazines - adverse effects; Oxazines - pharmacology; Pharmacology. Drug treatments; Ritonavir - adverse effects; Ritonavir - pharmacokinetics; Spectrophotometry, Ultraviolet
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1067/mcp.2002.121424

Objective This study evaluated the effect of multiple‐dose efavirenz on the steady‐state pharmacokinetics of the combination of indinavir (800 mg) and low‐dose ritonavir (100 mg) twice a day, in which ritonavir is used to increase indinavir plasma concentrations. Methods Eighteen healthy male volunteers participated in this multiple‐dose, 1‐arm, 2‐period interaction study. They took a combination of 800 mg indinavir and 100 mg ritonavir with food for 15 days. From days 15 to 29, a once‐daily administration of 600 mg efavirenz was added to the combination. Pharmacokinetics of indinavir and ritonavir on days 15 and 29 were compared. Results Fourteen volunteers completed the study. The addition of efavirenz resulted in significant reductions (P < .01) in indinavir area under the curve (AUC, −25%), trough concentration (Cmin, −50%), and maximum concentration (Cmax, −17%). All indinavir Cmin levels on day 29 remained equivalent to or above the mean Cmin value described for the regimen of 800 mg indinavir three times a day, without ritonavir (0.15 mg/L). Changes in ritonavir AUC, Cmin, and Cmax were −36%, −39%, and −34%, respectively. Pharmacokinetics of efavirenz on day 29 were comparable with published data. Conclusions The addition of efavirenz to a combination of 800 mg indinavir and 100 mg ritonavir twice daily results in significant decreases in AUC, Cmax, and especially Cmin of indinavir. The dose of indinavir or ritonavir should be increased to maintain similar indinavir drug levels after addition of efavirenz to the indinavir‐ritonavir combination. Dose modifications may not be needed in antiretroviral‐naive human immunodeficiency virus–infected patients if the reference Cmin of the regimen of 800 mg indinavir 3 times a day is considered to be adequate. Clinical Pharmacology & Therapeutics (2002) 71, 57–67; doi: 10.1067/mcp.2002.121424