Lack of an effect of human immunodeficiency virus coinfection on the pharmacokinetics of entecavir in hepatitis B virus-infected patients.
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 x 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.
Zhu
Min
M
Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton NJ 08543-4000, USA.
Bifano
Marc
M
Xu
Xu
X
Wang
Yonghua
Y
LaCreta
Frank
F
Grasela
Dennis
D
Pfister
Marc
M
D000465:Algorithms; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D006147:Guanine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D006509:Hepatitis B / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D016032:Randomized Controlled Trials as Topic
D000998:Antiviral Agents; C413685:entecavir; D006147:Guanine