Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Children With Chronic HCV: Part 2 of the DORA Study
Maureen M Jonas, Susan Rhee, Deirdre A Kelly, Antonio Del Valle-Segarra, Cornelia Feiterna-Sperling, Susan Gilmour, Regino P Gonzalez-Peralta, Loreto Hierro, Daniel H Leung, Simon C Ling, Yuri Lobzin, Steven Lobritto, Tatsuki Mizuochi, Michael R Narkewicz, Vishakha Sabharwal, Jessica Wen, Hoi Kei Lon, John Marcinak, Andrew Topp, Rakesh Tripathi, Etienne Sokal, Maureen M Jonas, Susan Rhee, Deirdre A Kelly, Antonio Del Valle-Segarra, Cornelia Feiterna-Sperling, Susan Gilmour, Regino P Gonzalez-Peralta, Loreto Hierro, Daniel H Leung, Simon C Ling, Yuri Lobzin, Steven Lobritto, Tatsuki Mizuochi, Michael R Narkewicz, Vishakha Sabharwal, Jessica Wen, Hoi Kei Lon, John Marcinak, Andrew Topp, Rakesh Tripathi, Etienne Sokal
Abstract
Background and aims: Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV-infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years.
Approach and results: Children with chronic HCV infection, genotype 1-6, with or without compensated cirrhosis, were divided into three cohorts by age-cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)-and given weight-based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady-state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug-related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults.
Conclusions: A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV-infected children 3 to < 12 years old.
Trial registration: ClinicalTrials.gov NCT03067129.
© 2021 by the American Association for the Study of Liver Diseases.
Figures
References
- Blach S, Zeuzem S, Manns M, Altraif I, Duberg A‐S, Muljono DH, et al. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol 2017;2:161‐176.
- Indolfi G, Hierro L, Dezsofi A, Jahnel J, Debray D, Hadzic N, et al. Treatment of chronic hepatitis C virus infection in children: a position paper by the Hepatology Committee of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018;66:505‐515.
- Indolfi G, Easterbrook P, Dusheiko G, El‐Sayed MH, Jonas MM, Thorne C, et al. Hepatitis C virus infection in children and adolescents. Lancet Gastroenterol Hepatol 2019;4:477‐487.
- Bortolotti F, Verucchi G, Cammà C, Cabibbo G, Zancan L, Indolfi G, et al. Long‐term course of chronic hepatitis C in children: from viral clearance to end‐stage liver disease. Gastroenterology 2008;134:1900‐1907.
- Leung DH, Squires JE, Jhaveri R, Kerkar N, Lin C‐H, Mohan P, et al. Hepatitis C in 2020: A North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition position paper. J Pediatr Gastroenterol Nutr 2020;71:407‐417.
- American Association for the Study of Liver Diseases, Infectious Diseases Society of America . HCV guidance: recommendations for testing, managing, and treating hepatitis C. . Revised December 10, 2019. Accessed August 9, 2020.
- Sovaldi (sofosbuvir) . EU Summary of Product Characteristics. Cork, Ireland: Gilead Sciences Ireland; 2019.
- Harvoni (ledipasvir and sofosbuvir) . EU Summary of Product Characteristics. Cork, Ireland: Gilead Sciences Ireland; 2020.
- Harvoni (ledipasvir and sofosbuvir) . US Prescribing Information. Foster City, CA; Gilead Sciences, Inc.; 2020.
- Sovaldi (sofosbuvir) . US Prescribing Information. Foster City, CA: Gilead Sciences, Inc.; 2020.
- Schwarz KB, Rosenthal P, Murray KF, Honegger JR, Hardikar W, Hague R, et al. Ledipasvir–sofosbuvir for 12 weeks in children 3 to <6 years old with chronic hepatitis C. Hepatology 2020;71:422‐430.
- Murray KF, Balistreri WF, Bansal S, Whitworth S, Evans HM, Gonzalez‐Peralta RP, et al. Safety and efficacy of ledipasvir–sofosbuvir with or without ribavirin for chronic hepatitis C in children ages 6‐11. Hepatology 2018;68:2158‐2166.
- Jonas MMRR, Romero R, Sokal EM, Rosenthal P, Verucchi G, Lin CH, et al. Safety and efficacy of sofosbuvir/velpatasvir in pediatric patients 6 to < 18 years old with chronic hepatitis C infection. Hepatology 2019;70(Suppl. 1):465A.
- Epclusa (velpatasvir and sofosbuvir) . US Prescribing Information. Foster City, CA; Gilead Sciences, Inc.; 2020.
- Mavyret (glecaprevir and pibrentasvir) . US Prescribing Information. North Chicago, IL; AbbVie Inc.; 2020.
- Maviret EU. Summary of Product Characteristics. North Chicago, IL; AbbVie Inc.; 2020.
- Wyles D, Poordad F, Wang S, Alric L, Felizarta F, Kwo PY, et al. Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: a partially randomized phase 3 clinical trial. Hepatology 2018;67:514‐523.
- Puoti M, Foster GR, Wang S, Mutimer D, Gane E, Moreno C, et al. High SVR12 with 8‐week and 12‐week glecaprevir/pibrentasvir therapy: an integrated analysis of HCV genotype 1‐6 patients without cirrhosis. J Hepatol 2018;69:293‐300.
- Brown RS Jr, Buti M, Rodrigues L, Chulanov V, Chuang WL, Aguilar H, et al. Glecaprevir/pibrentasvir for 8 weeks in treatment‐naive patients with chronic HCV genotypes 1‐6 and compensated cirrhosis: the EXPEDITION‐8 trial. J Hepatol 2020;72:441‐449.
- Rockstroh JK, Lacombe K, Viani RM, Orkin C, Wyles D, Luetkemeyer AF, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients coinfected with hepatitis C virus and human immunodeficiency virus type 1: the EXPEDITION‐2 study. Clin Infect Dis 2018;67:1010‐1017.
- Jonas MM, Squires RH, Rhee SM, Lin C‐W, Bessho K, Feiterna‐Sperling C, et al. Pharmacokinetics, safety, and efficacy of glecaprevir/pibrentasvir in adolescents with chronic hepatitis C virus: part 1 of the DORA study. Hepatology 2020;71:456‐462.
Source: PubMed