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.) C hronic hepatitis B virus (HBV) infection remains an important global health problem, with an estimated 350 to 400 million individuals affected worldwide (1). While infection of adults results in the majority of subjects clearing the virus, infants who are exposed perinatally predominately develop partial immunologic tolerance, with life-long, chronic infection in over 90% of cases (1). Children often exhibit an initial phase of the disease characterized by high viral loads but little evidence of liver damage (2). The subsequent immune active phase of HBV infection, however, is characterized by hepatic enzyme elevations, fibrosis, and necroinflammatory liver injury. Over decades, persistent HBV replication can result in cirrhosis, end-stage liver disease, and hepatocellular carcinoma.Antiviral therapy for HBV aims to slow the progression of liver disease by cessation or prolonged suppression of viral replication. Current treatments for chronic HBV include alfa interferon, pegylated alfa interferon, and orally bioavailable nucleoside and nucleotide analogues lamivudine, adefovir, tenofovir, entecavir, and telbivudine. Only alfa interferon, lamivudine, and adefovir have been approved by the U.S. FDA for pediatric use (3). Alfa interferon was shown to result in HBV e antigen (HBeAg) seroconversion and viral DNA clearance in 26% o...

Determination of telbivudine in the plasma of chronic hepatitis B patients in long‐term treatment by high‐performance liquid chromatographic–tandem mass spectrometry

“…A high‐pressure liquid chromatography (HPLC) assay was reported to estimate the LdT and its metabolites concentrations in HepG2 cells, which took 60 min for analysis (Hernandez‐Santiago et al, ). Then, HPLC with tandem mass (MS/MS) or UV detection were employed to investigate the pharmacokinetics, pharmacodynamics and safety of LdT by Zhou's group (Hu et al, ; Lai et al, ; Stein et al, ; Zhou et al, , , ; Zhou, Fielman, Lloyd, Chao, & Brown, ; Zhou, Lloyd, Chao, & Brown, ). The linear range was set to 10–5000 ng/mL in HPLC‐MS/MS method and 100–10,000 ng/mL in HPLC‐UV method with a long retention time.…”

Chronic hepatitis B in children: Therapeutic challenges and perspectives

“…Telbivudine is an enantiomer of nucleoside thymidine. Phase 1 study results were published in 2013 with telbivudine given to children aged 2 to 18 years old. Telbivudine was well tolerated, and all adverse events were mild.…”

Changes in serum alanine aminotransferase levels in telbivudine versus lamivudine treatment for chronic hepatitis B: A meta-analysis

“…[13][14][15] Treatment with LAM reduces ALT levels in patients who were positive for hepatitis B surface antigen (HBsAg), suggesting that LAM can inhibit HBV transmission and normalize ALT. 16 TBV has been shown to be more effective than LAM in the treatment of patients with CHB, [17][18][19] as well having a superior therapeutic response and resistance profile. 18,[20][21][22][23] The aim of the present meta-analysis was to compare the efficacy of TBV and LAM in the treatment of CHB (assessed via ALT levels and HBV DNA stratum).…”