Are Adult Doses of HCV Regimens Appropriate in Adolescents?
SAN FRANCISCO, CA—Adult doses of sofosbuvir plus ribavirin or ledipasvir/sofosbuvir provided comparable plasma exposures and tolerable safety profile in adolescents with hepatitis C virus (HCV) infection, reported Brian Kirby, PhD, from Gilead Sciences, Foster City, CA, at The Liver Meeting® 2015.
Once-daily sofosbuvir 400mg plus ribavirin or fixed-dose combination ledipasvir/sofosbuvir 90mg/400mg are regimens approved for HCV treatment in adult patients. Dr. Kirby and his team set out to confirm the appropriateness of adult doses in an adolescent population with HCV infection by evaluating the pharmacokinetics (PK) of sofosbuvir and ledipasvir/sofosbuvir.
The study enrolled adolescents 12–17 years of age weighing ≥45kg at baseline who received either sofosbuvir 400mg once daily plus weight-based ribavirin for 7 days (n=10) or ledipasvir/sofosbuvir 90mg/400mg once daily for 10 days (n=10).
Upon treatment completion, patients were continued on sofosbuvir plus ribavirin for 12 or 24 weeks or ledipasvir/sofosbuvir for 12 weeks. Intensive PK assessments were performed on Day 7 for sofosbuvir plus ribavirin or Day 10 for ledipasvir/sofosbuvir, calculating and comparing sofosbuvir, GS-331007 (predominant circulating metabolite) and ledipasvir PK parameters via ANOVA to exposures in the Phase 2/3 sofosbuvir or ledipasvir/sofosbuvir adult clinical programs with pre-defined equivalence boundaries of 50% to 200%. The safety profile was assessed periodically.
Study results demonstrated comparable PK parameters and safety profile between the adult and adolescent populations. Modestly higher GS-331007 (sofosbuvir plus ribavirin ) and ledipasvir (ledipasvir/sofosbuvir) Cmax values were found in adolescents, but such increases were "not considered clinically relevant based on established exposure-safety analyses," they noted.
Five patients in the sofosbuvir plus ribavirin arm and 3 in the ledipasvir/sofosbuvir arm experienced adverse events; none were Grade 3 or 4 or serious AEs and none led to permanent discontinuation of the study drug. In addition, there were "no Grade 2, 3 or 4 laboratory abnormalities" and no notable changes in vital signs were observed.
These short-term safety and PK data "support evaluation of sofosbuvir and ledipasvir/sofosbuvir adult clinical doses in adolescents," concluded Dr. Kirby.