{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T02:28:57Z","timestamp":1771468137351,"version":"3.50.1"},"reference-count":19,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T00:00:00Z","timestamp":1676332800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/ http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Patients and Methods:<\/jats:title>\n            <jats:p>We conducted a nonrandomized, single-arm, multicenter, open-label phase 2b trial in children and adolescents aged 3 to &lt;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 &lt;18\u00a0y), n=22; cohort 2 (aged 7 to &lt;12\u00a0y), n=17; and cohort 3 (aged 3 to &lt;7\u00a0y), n=18.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>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\u201324 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\u00a0wk 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/hc9.0000000000000031","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T15:00:26Z","timestamp":1676473226000},"page":"e0031-e0031","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":10,"title":["Elbasvir\/grazoprevir in children aged 3\u201318 years with chronic HCV genotype 1 or 4 infection: a pharmacokinetic modeling study"],"prefix":"10.1097","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0302-0982","authenticated-orcid":false,"given":"Regino P.","family":"Gonzalez-Peralta","sequence":"first","affiliation":[{"name":"AdventHealth for Children and AdventHealth Transplant Institute, Orlando, Florida, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8839-5315","authenticated-orcid":false,"given":"Stefan","family":"Wirth","sequence":"additional","affiliation":[{"name":"Helios University Hospital Wuppertal, Witten Herdecke University, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7330-2961","authenticated-orcid":false,"given":"Robert H.","family":"Squires","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine, UPMC Children\u2019s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1313-5863","authenticated-orcid":false,"given":"Frauke","family":"Mutschler","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Hepatology Hannover Medical School, Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5130-3365","authenticated-orcid":false,"given":"Thomas","family":"Lang","sequence":"additional","affiliation":[{"name":"Klinikum Starnberg, Starnberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6044-0425","authenticated-orcid":false,"given":"Malgorzata","family":"Pawlowska","sequence":"additional","affiliation":[{"name":"Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wojciech","family":"Sluzewski","sequence":"additional","affiliation":[{"name":"Karol Marcinkowski University of Medical Sciences, Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7178-5293","authenticated-orcid":false,"given":"Ewa","family":"Majda-Stanislawska","sequence":"additional","affiliation":[{"name":"Medical University of Lodz, Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8838-324X","authenticated-orcid":false,"given":"Bjorn","family":"Fischler","sequence":"additional","affiliation":[{"name":"Karolinska Institutet CLINTEC and Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7051-8839","authenticated-orcid":false,"given":"William F.","family":"Balistreri","sequence":"additional","affiliation":[{"name":"Cincinnati Children\u2019s Hospital, Cincinnati, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0962-3020","authenticated-orcid":false,"given":"Maureen M.","family":"Jonas","sequence":"additional","affiliation":[{"name":"Boston Children\u2019s Hospital, Boston, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5122-0706","authenticated-orcid":false,"given":"Niviann","family":"Blondet","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Hospital and the University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7840-5401","authenticated-orcid":false,"given":"Philip","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, San Francisco, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9872-2391","authenticated-orcid":false,"given":"Naim","family":"Alkhouri","sequence":"additional","affiliation":[{"name":"Texas Liver Institute, University of Texas Health, San Antonio, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1566-2280","authenticated-orcid":false,"given":"Rene","family":"Romero","sequence":"additional","affiliation":[{"name":"Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7339-8740","authenticated-orcid":false,"given":"Anjana","family":"Grandhi","sequence":"additional","affiliation":[{"name":"Merck & Co. Inc., Rahway, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1893-9804","authenticated-orcid":false,"given":"Patricia","family":"Castronuovo","sequence":"additional","affiliation":[{"name":"Merck & Co. Inc., Rahway, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2275-8771","authenticated-orcid":false,"given":"Luzelena","family":"Caro","sequence":"additional","affiliation":[{"name":"Merck & Co. Inc., Rahway, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2423-2060","authenticated-orcid":false,"given":"Lihong","family":"Du","sequence":"additional","affiliation":[{"name":"Merck & Co. Inc., Rahway, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1413-3907","authenticated-orcid":false,"given":"Daniel I.S.","family":"Rosenbloom","sequence":"additional","affiliation":[{"name":"Merck & Co. Inc., Rahway, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6315-5470","authenticated-orcid":false,"given":"Barbara A.","family":"Haber","sequence":"additional","affiliation":[{"name":"Merck & Co. Inc., Rahway, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2023,3]]},"reference":[{"key":"R1-20240826","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S2468-1253(19)30046-9","article-title":"Hepatitis C virus infection in children and adolescents","volume":"4","author":"Indolfi","year":"2019","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"R2-20240826","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/S2468-1253(19)30385-1","article-title":"Global prevalence of hepatitis C virus in children in 2018: a modelling study","volume":"5","author":"Schmelzer","year":"2020","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"R3-20240826","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1002\/hep.28995","article-title":"The safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12\u201317 years old with hepatitis C virus genotype 1 infection","volume":"66","author":"Balistreri","year":"2017","journal-title":"Hepatology"},{"key":"R4-20240826","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1002\/hep.30123","article-title":"Safety and efficacy of ledipasvir-sofosbuvir with or without ribavirin for chronic hepatitis C in children ages 6-11","volume":"68","author":"Murray","year":"2018","journal-title":"Hepatology"},{"key":"R5-20240826","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1002\/hep.30830","article-title":"Ledipasvir-sofosbuvir for 12 weeks in children 3 to <6 years old with chronic hepatitis C","volume":"71","author":"Schwarz","year":"2020","journal-title":"Hepatology"},{"key":"R6-20240826","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/hep.30821","article-title":"Sofosbuvir and ribavirin therapy for children aged 3 to <12 years with hepatitis C virus genotype 2 or 3 infection","volume":"71","author":"Rosenthal","year":"2020","journal-title":"Hepatology"},{"key":"R7-20240826","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1002\/hep.30840","article-title":"Pharmacokinetics, safety, and efficacy of glecaprevir\/pibrentasvir in adolescents with chronic hepatitis C virus: Part 1 of the DORA Study","volume":"71","author":"Jonas","year":"2020","journal-title":"Hepatology"},{"key":"R8-20240826","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1002\/hep.31060","article-title":"Hepatitis C guidance 2019 update: American Association for the Study of Liver Diseases\u2013Infectious Diseases Society of America recommendations for testing, managing, and treating hepatitis C virus infection","volume":"71","author":"Ghany","year":"2020","journal-title":"Hepatology"},{"key":"R11-20240826","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1080\/14787210.2021.1874351","article-title":"Elbasvir and grazoprevir for the treatment of hepatitis C","volume":"19","author":"Wang","year":"2021","journal-title":"Expert Rev Anti Infect Ther"},{"key":"R12-20240826","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1111\/jvh.13357","article-title":"Safety and tolerability of elbasvir\/grazoprevir in chronic hepatitis C virus therapy: integrated analysis from clinical trials","volume":"27","author":"Nangia","year":"2020","journal-title":"J Viral Hepat"},{"key":"R13-20240826","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7326\/M15-0785","article-title":"Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, 4, or 6 infection: a randomized trial","volume":"163","author":"Zeuzem","year":"2015","journal-title":"Ann Intern Med"},{"key":"R14-20240826","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1053\/j.gastro.2016.09.045","article-title":"Effectiveness of elbasvir and grazoprevir combination, with or without ribavirin, for treatment-experienced patients with chronic hepatitis C infection","volume":"152","author":"Kwo","year":"2017","journal-title":"Gastroenterology"},{"key":"R15-20240826","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1016\/S0140-6736(15)00349-9","article-title":"Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study","volume":"386","author":"Roth","year":"2015","journal-title":"Lancet"},{"key":"R16-20240826","doi-asserted-by":"crossref","first-page":"e319","DOI":"10.1016\/S2352-3018(15)00114-9","article-title":"Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial","volume":"2","author":"Rockstroh","year":"2015","journal-title":"Lancet HIV"},{"key":"R17-20240826","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s40262-013-0041-1","article-title":"Developmental changes in the expression and function of cytochrome P450 3A isoforms: evidence from in vitro and in vivo investigations","volume":"52","author":"Ince","year":"2013","journal-title":"Clin Pharmacokinet"},{"key":"R18-20240826","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1124\/dmd.113.053819","article-title":"Interindividual variability in hepatic organic anion-transporting polypeptides and P-glycoprotein (ABCB1) protein expression: quantification by liquid chromatography tandem mass spectroscopy and influence of genotype, age, and sex","volume":"42","author":"Prasad","year":"2014","journal-title":"Drug Metab Dispos"},{"issue":"suppl 1","key":"R19-20240826","first-page":"S104","article-title":"Role of model-informed drug development in pediatric drug development, regulatory evaluation, and labeling","volume":"59","author":"Bi","year":"2019","journal-title":"J Clin Pharmacol"},{"key":"R20-20240826","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1002\/cpt.1886","article-title":"Combined pediatric and adult trials submitted to the US Food and Drug Administration 2012\u20132018","volume":"108","author":"Tanaudommongkon","year":"2020","journal-title":"Clin Pharmacol Ther"},{"key":"R22-20240826","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1111\/liv.13727","article-title":"Efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 4 infection: a pooled analysis","volume":"38","author":"Asselah","year":"2018","journal-title":"Liver Int"}],"container-title":["Hepatology Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/HC9.0000000000000031","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T15:07:12Z","timestamp":1724684832000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/HC9.0000000000000031"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,14]]},"references-count":19,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023]]}},"URL":"https:\/\/doi.org\/10.1097\/hc9.0000000000000031","relation":{},"ISSN":["2471-254X"],"issn-type":[{"value":"2471-254X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,14]]},"assertion":[{"value":"2022-06-16","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-15","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}