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

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Abstract
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.