Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Hepatic Impairment

Abstract

This study evaluated the effect of hepatic impairment on the pharmacokinetics of telbivudine, an investigational nucleoside antiviral for the treatment of chronic hepatitis B virus infection. Twenty-four subjects were assigned to four hepatic function groups (normal function and mild, moderate, and severe impairment, with six subjects in each group) on the basis of Child-Pugh scores. The subjects were administered a single oral dose of 600 mg telbivudine, and blood samples were collected over a 48-h interval for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. Telbivudine plasma concentration-time profiles were similar across the four hepatic function groups. The principal pharmacokinetic parameters of drug exposure, i.e., the maximum plasma concentration and area under the drug concentration-time curve, were comparable between subjects with various degrees of hepatic impairment and those with normal hepatic function. Results from this single-dose pharmacokinetic assessment therefore provide a pharmacologic rationale for further evaluation of the safety and efficacy of telbivudine in hepatitis B virus-infected patients with decompensated liver diseases.

Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Renal Impairment

“…Blood samples (ϳ7 ml at each time point) were collected into heparinized Vacutainer blood collection tubes immediately before (0 h) and at 0.5, 0.75, 1,2,3,4,8,12,16,20,24,28,32,36, and 48 h after dosing from all subjects, including those with ESRD with postdialysis dosing. Blood samples for subjects with predialysis dosing were collected immediately before dosing (0 h) and at 0.5, 0.75, 1, and 2 (start of dialysis), 3.75 to 4 (mid-dialysis), 5.5 to 6 (end of dialysis), 8,12,16,20,24,28,32,36, and 48 h after dosing. At these start-, middle-, and end-of-dialysis time points, paired pre-and postdialyzer samples were collected to assess the effect of hemodialysis in removing telbivudine.…”

“…Hepatic impairment has no effect on telbivudine pharmacokinetics (12). In vitro, telbivudine is converted efficiently into high concentrations of its active 5Ј-triphosphate derivative in the HepG2 cell line and in human hepatocytes in primary culture (4,8).…”

“…Telbivudine exhibits dose-proportional pharmacokinetics with respect to the maximum concentration of the drug in plasma (C max ) and the area under the plasma concentrationtime curve (AUC), and a biphasic plasma disposition (5,10). Concentrations in blood at steady state are approximately 50% higher than those obtained after single dosing, owing to a second-phase elimination that starts more than 12 h after dosing (5,11,12). Telbivudine has a long terminal half-life (t 1/2 ) of approximately 40 to 50 h during this second elimination phase, indicating a sustained exposure to the drug that supports oncedaily dosing (5).…”

“…Telbivudine undergoes minimal hepatic metabolism and is eliminated primarily by renal clearance as the unchanged drug (1,12). Hepatic impairment has no effect on telbivudine pharmacokinetics (12).…”

“…Telbivudine is absorbed rapidly following oral administration, reaching maximum concentrations in plasma at ϳ3 h (5,(9)(10)(11)(12). Telbivudine exhibits dose-proportional pharmacokinetics with respect to the maximum concentration of the drug in plasma (C max ) and the area under the plasma concentrationtime curve (AUC), and a biphasic plasma disposition (5,10).…”