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DRUG INTERACTIONS

Darunavir/Ritonavir Pharmacokinetics Following Coadministration With Clarithromycin in Healthy Volunteers

Vanitha J. Sekar, PhD, Sabrina Spinosa-Guzman, MD, Els De Paepe, MSc, Martine De Pauw, PharmD, Tony Vangeneugden, MSc, Eric Lefebvre, MD and Richard M. W. Hoetelmans, PharmD, PhD

From Tibotec, Inc, Yardley, Pennsylvania (Dr Sekar); Tibotec BVBA, Mechelen, Belgium (Dr Spinosa-Guzman Mr De Paepe, Dr De Pauw, Mr Vangeneugden, Dr Hoetelmans); and Janssen-Cilag, Tilburg, The Netherlands (Dr Lefebvre). Some of these data were presented at the 2006 annual meeting of the American Society for Clinical Pharmacology and Therapeutics, March 8-11, 2006, Baltimore, Maryland (Poster PI-61). Dr Sekar is a member of the American College of Clinical Pharmacology.

This study investigated the steady-state pharmacokinetic interaction between the HIV protease inhibitor, darunavir (TMC114), administered with low-dose ritonavir (darunavir/ritonavir), and clarithromycin in HIV-negative healthy volunteers. In a 3-way crossover study, 18 individuals received darunavir/ritonavir 400/100 mg bid, clarithromycin 500 mg bid, and darunavir/ritonavir 400/100 mg bid plus clarithromycin 500 mg bid in 3 separate sessions for 7 days, with a washout period of at least 7 days between treatments. Pharmacokinetic assessment was performed on day 7. Safety and tolerability of the study medication were monitored throughout. Coadministration of darunavir/ritonavir with clarithromycin resulted in a reduction in darunavir maximum plasma concentration (Cmax) and area under the curve from administration until 12 hours postdose (AUC12 h) of 17% and 13%, respectively. Ritonavir Cmax and AUC12 h were unchanged. During coadministration with darunavir/ritonavir, clarithromycin Cmax and AUC12 h increased by 26% and 57%, respectively; 14-hydroxy-clarithromycin plasma concentrations were reduced to below the lower limit of quantification (<50 ng/mL). The study medication was generally well tolerated. Based on these pharmacokinetic findings, neither clarithromycin nor darunavir/ritonavir dose adjustments are necessary when clarithromycin is coadministered with darunavir/ritonavir.

Key Words: Darunavir • TMC114 • clarithromycin • pharmacokinetic interaction • HIV

Address for reprints: Vanitha J. Sekar, Tibotec, Inc, 1020 Stony Hill Road, Yardley, PA 19067; e-mail: vsekar{at}tibus.jnj.com.


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