Elbasvir/grazoprevir in children aged 3-18 years with chronic HCV genotype 1 or 4 infection: a pharmacokinetic modeling study

Abstract

Background: Approximately 3.5 million children and adolescents worldwide are chronically infected with HCV. This study uses pharmacokinetic modeling to identify pediatric doses of elbasvir/grazoprevir (EBR/GZR) that achieve plasma concentrations similar to those seen in adults receiving the approved fixed-dose combination regimen of EBR/GZR.

Patients and methods: We conducted a nonrandomized, single-arm, multicenter, open-label phase 2b trial in children and adolescents aged 3 to <18 years with chronic HCV genotype 1 or 4 infection (NCT03379506). Pharmacokinetic data were used to bridge efficacy and safety data from adults to children in a stepwise (oldest to youngest) manner. A total of 57 participants were enrolled: cohort 1 (aged 12 to <18 y), n=22; cohort 2 (aged 7 to <12 y), n=17; and cohort 3 (aged 3 to <7 y), n=18.

Results: Steady-state plasma exposures were achieved by week 4 for EBR and GZR in all cohorts and daily dosing achieved geometric mean steady-state area under the concentration-time curve at 0-24 hours that fell within comparability bounds established for adults. All participants achieved sustained virologic response 12 weeks after completing treatment (ie, undetectable HCV RNA 12 wk following completion of treatment). Headache (n=4), fatigue (n=4), and nausea (n=2) were the most common treatment-related adverse events (all mild or moderate); no participant discontinued because of an adverse event.

Conclusions: Pediatric EBR/GZR pharmacokinetic models were successfully developed based on complex adult population pharmacokinetic models. At appropriate age-related doses, EBR/GZR is safe and effective in pediatric and adolescent participants with HCV infection.

Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.

Figures

Figure 1

EBR and GZR AUC0–24 at steady state (week 4) for mini cohorts 1–3. Abbreviations: AUC0–24, area under the concentration-time curve at 0–24 hours; EBR, elbasvir; FDC, fixed-dose combination; Geo., geometric; GZR, grazoprevir; QD, once daily.

Figure 2

EBR and GZR AUC0–24 at steady state (week 4) for mini cohorts 1 and 2 and expanded cohorts 1–3. EBR and GZR exposures following adjusted dosing in expanded cohort 3 are shown (EBR 25 mg; GZR 50 mg); initial exposures obtained in mini cohort 3 before dose adjustment are shown in Figure 1. Abbreviations: AUC0–24, area under the concentration-time curve at 0–24 hours; EBR, elbasvir; FDC, fixed-dose combination; Geo., geometric; GZR, grazoprevir; QD, once daily.

Figure 3

Arithmetic mean plasma concentrations of EBR (A) and GZR (B) at days 1, 28, and 56. Abbreviations: EBR, elbasvir; FDC, fixed-dose combination; GZR, grazoprevir; QD, once daily.

Figure 4

SVR12 and SVR24 with EBR/GZR in cohorts 1–3. Abbreviations: EBR, elbasvir; GZR, grazoprevir; SVR, sustained virologic response; SVR12, sustained virologic response at 12 weeks after completion of therapy; SVR24, sustained virologic response at 24 weeks after completion of therapy.