Phase I, open-label, single-dose study to evaluate the pharmacokinetics and safety of telbivudine in children and adolescents with chronic hepatitis B

Abstract

Telbivudine is a nucleoside analogue that has been approved for the treatment of chronic hepatitis B virus (HBV) infection in adults at 600 mg/day. We conducted a phase I, open-label, first-in-pediatrics study to investigate the safety and pharmacokinetics of a single dose of telbivudine in HBV-infected children and adolescents. Eligible patients were enrolled sequentially from older to younger groups, with evaluation of safety and available pharmacokinetic data after each stratum. Adolescent patients (>12 to 18 years) received a single dose of 600 mg telbivudine as an oral solution, while children aged 2 to 12 years received a single dose of 15 or 25 mg/kg of body weight up to a maximum of 600 mg. Telbivudine was well tolerated; all adverse events were mild, and none occurred in more than one patient. The plasma telbivudine concentration-versus-time profiles in adolescents given 600 mg were similar to the mean profile of healthy adults receiving the same oral dose. Children aged 2 to <6 and 6 to 12 years receiving a single 15-mg/kg dose showed similar plasma exposures. To predict the steady-state exposure, plasma concentration-versus-time profiles for patients aged 2 to 12 years (15 mg/kg) and >12 to 18 years (600 mg) were fitted to a two-compartment 1st-order, microconstant, lag time, 1st-order elimination pharmacokinetic (PK) model. This analysis predicted the following dosages to mimic exposures in healthy adults receiving 600 mg/day: 20 mg/kg/day for children 2 to 12 years and 600 mg/day for adolescents. Studies are ongoing to evaluate the efficacy of the recommended dose in pediatric patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00907894.).

Figures

Fig 1

Comparison of plasma telbivudine concentration-versus-time profiles of children to historical adult data. Black symbols are plasma telbivudine concentrations from individual children aged >12 to 18 years (600 mg, n = 8) (A), 6 to 12 years (15 mg/kg, n = 4) (B), 6 to 12 years (25 mg/kg, n = 4) (C), and 2 to <6 years (15 mg/kg, n = 6) (D). White symbols and lines represent mean (±standard deviation) historical plasma telbivudine concentrations in adults (n = 23) receiving a single 600-mg oral dose.