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Antimicrobial Agents and Chemotherapy, August 2008, p. 2836-2841, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.01366-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Lack of an Effect of Human Immunodeficiency Virus Coinfection on the Pharmacokinetics of Entecavir in Hepatitis B Virus-Infected Patients{triangledown}

Min Zhu, Marc Bifano, Xu Xu, Yonghua Wang, Frank LaCreta, Dennis Grasela, and Marc Pfister*

Bristol-Myers Squibb Research and Development, Princeton, New Jersey

Received 23 October 2007/ Returned for modification 14 January 2008/ Accepted 27 March 2008

Entecavir is a guanosine nucleoside analogue approved for the treatment of chronic hepatitis B virus (HBV) infection. The impact of human immunodeficiency virus (HIV) coinfection on the pharmacokinetics (PK) of entecavir was examined by nonlinear mixed-effects modeling. Plasma concentration data from HIV- and HBV-coinfected patients were analyzed in conjunction with data from HBV-monoinfected patients, and HIV coinfection was tested as a covariate on oral clearance (CL/F). The estimated population averages of intercompartmental clearance and the volumes of distribution in the central and peripheral compartments obtained with a 1-mg dose were 34.2 liters/h (interindividual variability, 30.2%), 115 liters (interindividual variability, 39.2%), and 1,830 liters (interindividual variability, 74%), respectively. CL/F was found to be a function of creatinine clearance, but HIV confection did not show any effect on CL/F. The geometric mean (GM) of individual Bayesian estimates of the steady-state area under the concentration-time curve following 1-mg daily doses were 39.3 and 38.8 ng·h/ml in HIV- and HBV-coinfected and HBV-monoinfected patients, respectively. The adjusted GM ratio (1.01; 90% confidence interval, 0.91 to 1.12) was within the bioequivalence criteria boundary (0.80 to 1.25). In conclusion, the proposed model adequately described the entecavir PK in HBV- and HIV-coinfected patients and HBV-monoinfected patients, and the entecavir exposures were comparable in the two patient populations.

* Corresponding author. Mailing address: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton NJ 08543-4000. Phone: (609) 252-7822. Fax: (609) 252-5322. E-mail: marc.pfister{at}bms.com

{triangledown} Published ahead of print on 7 April 2008.

Antimicrobial Agents and Chemotherapy, August 2008, p. 2836-2841, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.01366-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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