Beta-thalassemia major alters sofosbuvir/ledipasvir exposure in Hepatitis C virus infected adolescent patients

Authors: El-Baraky I, Abassi M, Hassany M, Sabry N, El-Sayed M
Publication: Clin Res Hepatology Gastroenterology
Keywords: Hepatitis C virus, Ledipasvir, pharmacokinetics, Sofosbuvir, Thalassemia
Software: PKanalix®
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Background

Hepatitis C virus (HCV) infected adolescents with beta-thalassemia major (BTM) are considered a potential population for HCV micro-elimination model development where BTM may negatively impact the pharmacokinetic exposure parameters of sofosbuvir/ledipasvir (SOF/LED).

Objectives

The study aimed at studying the effect of BTM on SOF/LED and SOF metabolite (GS-331007) pharmacokinetics.

Methods

A prospective, controlled study recruiting BTM and control HCV infected adolescents (Clinicaltrials.gov identifier-NCT04353986). Pharmacokinetic exposure to GS-331007 and LED was the primary pharmacokinetic outcome. No-effect boundaries were set to 90% confidence interval (CI) of exposure geometric mean ratio (GMR) within 70–143%. Dose suitability was based on the 90% CI of exposure GMR within 50-200% compared to adults. The percentage of patients achieving sustained virologic response 12 weeks post-treatment (SVR12) was the primary efficacy endpoint.

Results

Thirteen patients were enrolled per study group. All patients were included in the pharmacokinetic analysis (n=26). BTM patients showed lower GS-331007 and LED exposure that could, respectively, be as low as 45.4% and 36.1% compared to their control group. GS-331007 exposure in BTM patients was nearly half (56.8%, 90% CI 45.3–71.2%) that observed in adults. Despite that low drug exposure in 46.2% of BTM patients may alert dose unsuitability, they achieved SVR12. Moreover, patients with total bilirubin ≥1.93 mg/dL were predicted to have low GS-331007 exposure (0.913 receiver operating characteristic area under the curve with sensitivity and specificity >80%).

Conclusion and Relevance

The identified systematically lower drug exposure in BTM patients might partially explain relapses or treatment failures among BTM patients reported in other studies. BTM may be a hurdle towards implementing HCV micro-elimination model that may necessitate dose-adjustment.

By Iman A. El-Baraky, Maggie M. Abbassi, Fatma S. Ebeid, Mohamed Hassany, Nirmeen A. Sabry, Manal H. El-Sayed