Presentation Abstract

Session: 016-HIV Pharmacology
Saturday, Sep 12, 2009, 11:30 AM - 1:30 PM
Presentation Title: H-230 - Assessment of Pharmacokinetic and Safety Interactions Between Vicriviroc and CYP3A4 Substrates, Inhibitors, and Inducers
Location: Hall B
Poster Board Number: 246
Presentation Number: H-230
Pres. Time: Saturday, Sep 12, 2009, 11:30 AM - 1:30 PM
Category: H
Keywords: HIV therapy; pharmacokinetics; safety
Author(s): C. KASSERRA1, E. O'MARA 1, E. LISBON 2;
1Schering-Plough Res. Inst., Kenilworth, NJ, 2Quintiles, Inc., Overland Park, KS.
Abstract: Background: The objective of this study was to investigate vicriviroc (VCV) as a CYP3A4 substrate or inhibitor/inducer. Drugs evaluated included midazolam (MDZ), a CYP3A4 substrate; ketoconazole (keto), a CYP3A4 inhibitor; the antituberculosis drugs rifabutin and rifampin, and the anticonvulsant carbamazepine (CBZ). Rifabutin, rifampin, and CBZ are all CYP3A4 inducers and potential concomitant medications with VCV. Methods: This open-label, drug-interaction study was conducted at a single center in 74 healthy adults. Each part of the study was a fixed-sequence one-way crossover design with VCV at a dose of 30 mg, with or without ritonavir (RTV). Results: MDZ exposure was not affected by VCV administered alone, but was markedly increased when VCV was administered with RTV, a potent CYP3A4 inhibitor. Exposure of VCV was substantially increased (503% based on AUC) when administered concomitantly just with keto, while keto only modestly increased VCV concentrations (136% based on AUC) in the presence of RTV, compared to VCV alone. Rifabutin did not alter VCV exposure when dosed with 200 mg QD RTV. Rifampin, a potent CYP3A4 inducer, markedly decreased VCV exposure when dosed with 100 mg BID RTV; the relative oral bioavailability of VCV + RTV with rifampin compared to VCV + RTV alone was 11.6% based on AUC. Carbamazepine did not alter VCV exposure when dosed with 100 mg BID RTV. Conclusions: VCV is not itself a CYP3A4 inhibitor/inducer, but is a CYP3A4 substrate. However, in the presence of RTV, addition of another CYP3A4 inhibitor or modestly potent CYP3A4 inducer will not require VCV dose adjustment. If CBZ or rifabutin are coadministered with VCV in a RTV-boosted PI-containing regimen, no VCV dose adjustment is required, but the RTV dose should be increased, to 100 mg BID or 200 mg QD. Coadministration of rifampin with VCV is not recommended. Vicriviroc with or without RTV was safe and well tolerated alone or coadministered with the drugs used in this study.

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