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Pharmacokinetic interaction between voriconazole and ritonavir at steady state in healthy subjects
Author(s) -
Liu P.,
Foster G.,
Labadie R.,
Allison M. J.,
Sharma A.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.045
Subject(s) - pharmacokinetics , cmax , ritonavir , placebo , medicine , pharmacology , cyp3a4 , anesthesia , cytochrome p450 , human immunodeficiency virus (hiv) , metabolism , viral load , antiretroviral therapy , alternative medicine , family medicine , pathology
Aim Voriconazole (VORI), a triazole antifungal agent, is metabolized by the cytochrome P450 CYP2C19, CYP2C9, and to a lesser extent by CYP3A4. Ritonavir (RITO), a protease inhibitor, is primarily metabolized by the CYP3A4. This study was conducted to evaluate the pharmacokinetic interactions between these two compounds. Methods A randomized, subject and investigator blinded with respect to VORI, placebo controlled (VORI only), parallel group, two‐period multiple‐dose study was conducted in 34 healthy male subjects. In Period 1, subjects received therapeutic doses of VORI (400 mg twice daily (BID) on day 1 followed by 200 mg BID) or placebo for 3 days. After a 7‐day washout, subjects received 400 mg BID RITO for 20 days in Period 2. After 10 days of RITO alone, therapeutic dose of VORI or placebo were co‐administered for the next 10 days. The steady state pharmacokinetics of VORI and RITO following 10 days of co‐administration were compared to those of VORI alone and RITO alone, respectively. Results RITO decreased the mean steady state area under the concentration‐time curve from time 0 to tau (AUC 0–12 ) of VORI by 82% (26500 vs. 4250 ng·hr/mL, P< 0.001), and the mean steady state peak plasma concentration (C max ) of VORI by 66% (3600 vs. 1220 ng/mL, P <0.001). VORI had no effect on the steady state RITO pharmacokinetics. Conclusions Co‐administration of VORI with RITO should be contraindicated due to the clinically significant effect of RITO on VORI pharmacokinetics. Clinical Pharmacology & Therapeutics (2005) 77 , P40–P40; doi: 10.1016/j.clpt.2004.12.045