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Antimicrobial Agents and Chemotherapy, March 2006, p. 874-879, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.874-879.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of Telbivudine following Oral Administration of Escalating Single and Multiple Doses in Patients with Chronic Hepatitis B Virus Infection: Pharmacodynamic Implications

Xiao-Jian Zhou,1* Seng-Gee Lim,2 Deborah M. Lloyd,1 George C. Chao,1 Nathaniel A. Brown,1 and Ching-Lung Lai3

Idenix Pharmaceuticals Inc., 60 Hampshire Street, Cambridge, Massachusetts 02139,1 National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore,2 Division of Hepatology, University of Hong Kong, Queen Mary Hospital, 102 Pok Fu Lam Road, Pok Fu Lam, Hong Kong, China3

Received 11 July 2005/ Returned for modification 1 September 2005/ Accepted 8 December 2005

The pharmacokinetics of telbivudine were evaluated in adult patients with chronic hepatitis B virus (HBV) infection following once-daily oral administration at escalating doses of 25, 50, 100, 200, 400, and 800 mg/day for 4 weeks. Telbivudine was rapidly absorbed after oral administration, with the median times Tmax to the maximum plasma concentration (Cmax) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum Cmaxs and the areas under the plasma concentration-time curve from time zero to time t (AUC0-ts) increased proportionally with dose. At steady-state, the values of Cmax and AUC0-t were higher than those obtained after the administration of a single dose, indicative of a slight accumulation, with the ratios of the steady-state value to the value after the administration of a single dose ranging from 1.14 to 1.49 for Cmax and from 1.40 to 1.70 for AUC0-t. While the elimination of telbivudine from plasma was apparently monophasic over the 8-h sampling period, the substantial steady-state trough plasma levels observed in the groups receiving doses of 100 to 800 mg were clearly indicative of the presence of a second slower elimination phase, with the mean estimated half-lives ranging from 29.5 to 41.3 h by compartmental modeling analysis. Pharmacokinetic and pharmacodynamic analyses by using maximum-effect modeling established a quantitative relationship between a reduction in serum HBV DNA levels and parameters of drug exposure, in particular, the steady-state Cmax and AUC0-t. In summary, this study showed that telbivudine exhibits dose-proportional plasma pharmacokinetics with sustained steady-state drug exposure and exposure-related antiviral activity, supporting the need for further clinical studies by use of a once-daily regimen in patients with chronic HBV infection.

* Corresponding author. Mailing address: Idenix Pharmaceuticals Inc., 60 Hampshire Street, Cambridge, MA 02139. Phone: (617) 995-9805. Fax: (617) 995-9801. E-mail: zhou.xiao-jian{at}idenix.com.

Antimicrobial Agents and Chemotherapy, March 2006, p. 874-879, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.874-879.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Scarsi, K. K., Darin, K. M. (2009). Chronic Hepatitis B Infection: Principles of Therapy. Journal of Pharmacy Practice 22: 359-387 [Abstract]  
  • Zhou, X.-J., Ke, J., Sallas, W. M., Farrell, C., Mayers, D. L., Pentikis, H. S. (2009). Population Pharmacokinetics of Telbivudine and Determination of Dose Adjustment for Patients With Renal Impairment. J Clin Pharmacol 49: 725-734 [Abstract] [Full Text]  
  • Dusheiko, G, Antonakopoulos, N (2008). Current treatment of hepatitis B. Gut 57: 105-124 [Full Text]  
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