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

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 T max to the maximum plasma concentration (C max ) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum C max s and the areas under the plasma concentration-time curve from time zero to time t (AUC 0-t s) increased proportionally with dose. At steady-state, the values of C max and AUC 0-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 C max and from 1.40 to 1.70 for AUC 0-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 C max and AUC 0-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.Telbivudine (␤-L-2Ј-deoxythymidine) is an L-configured nucleoside with potent and specific activities against hepatitis B virus (HBV) and other hepadnaviruses and no appreciable activity against human immunodeficiency virus or other viruses (3). The in vitro median effective concentration of telbivudine for reducing extracellular DNA levels in HBV-expressing hepatoma cell line 2.2.15 was 0.19 M (ϳ0.05 g/ml). In woodchucks chronically infected with woodchuck HBV, up to 28 days of telbivudine treatment produced consistent, multilog reductions in circulating serum woodchuck HBV DNA levels (3).In vitro toxicological assessments produced no adverse findings (1-3). The 50% cytotoxic concentration of telbivudine in 2.2.15 cells was Ͼ2,00 M (ϳ500 g/ml), indicating that it has an excellent therapeutic index in cell culture (3). Other in vitro results suggested that telbivudine is unlikely to be associated with hematologic or mitochondrial toxicities, peripheral neuropathy, or myopathy (3). Mutagenic test results were negative (1).Acute and subchronic toxicology studies did not identify any preclinical safety issues for telbivudine. In acute and subchronic (28-day) toxicity studies conducted with rats ...

Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Hepatic Impairment

“…In addition, data from a phase I/II trial with HBV-infected patients showed that telbivudine exhibited doseproportional pharmacokinetics and an exposure-related viral response, with nearly maximum antiviral effects achieved with telbivudine doses in the range of 400 to 800 mg/day (10,18). No dose-limiting toxicities were observed in that trial over the dose range studied, 25 to 800 mg/day (10).…”

“…Pharmacokinetic studies with healthy subjects and HBVinfected patients demonstrated that following oral dosing, telbivudine is rapidly absorbed, with maximum plasma concentrations (C max ) reached within 1 to 3 h (16,17,18,19). Following intravenous and oral administration of telbivudine at 10 mg/kg to cynomolgus monkeys, 77.0% and 36.6% of the administered drug, respectively, was eliminated in the urine within 14 days (unpublished data).…”

Pharmacokinetics of Telbivudine in Healthy Subjects and Absence of Drug Interaction with Lamivudine or Adefovir Dipivoxil

“…Incorporation of the 5Ј-triphosphorylated telbivudine into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication (1). Recent clinical trials in adults with chronic HBV have established that once-daily telbivudine is well tolerated by patients and exhibits dose-dependent potent antiviral activity (12,13,21).…”

Clinical features of adverse reactions associated with telbivudine

“…This suggests that myalgia is dose-dependent. Other studies [24][25][26][27] have shown that telbivudine plasma concentration is correlated with dosage when in the range 200-600 mg/d. As a result of the long half-life of this drug, a dose of 600 mg twice daily may lead to drug accumulation.…”