{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:41:24Z","timestamp":1790361684330,"version":"4.1.0"},"reference-count":20,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T00:00:00Z","timestamp":1688947200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP21ek0109513"],"award-info":[{"award-number":["JP21ek0109513"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Achondroplasia (ACH) is a common skeletal dysplasia characterized by a disproportionately short stature. We found that meclizine, which is an over-the-counter drug for motion sickness, inhibited the fibroblast growth factor receptor 3 (FGFR3) gene using a drug repositioning strategy, and meclizine 1 and 2 mg\/kg\/day promoted bone growth in a mouse model of ACH. A previous phase 1a clinical trial for children with ACH demonstrated that a single dose of meclizine 25 and 50 mg was safe and that the simulated plasma concentration achieved steady state approximately 10 days after the first dose. The current study aimed to evaluate the safety and pharmacokinetics (PK) of meclizine in children with ACH after a 14-day-repeated dose of meclizine. Twelve patients with ACH aged 5\u201310 years were enrolled. Meclizine 12.5 (cohort 1) and 25 mg\/day (cohort 2) were administered after meals for 14 days, and adverse events (AEs) and PK were evaluated. No patient experienced serious AEs in either group. The average (95% confidential interval [CI]) maximum drug concentration (C<jats:sub>max<\/jats:sub>), peak drug concentration (T<jats:sub>max<\/jats:sub>), area under the curve (AUC) from 0 to 24 h, and terminal elimination half-life (t<jats:sub>1\/2<\/jats:sub>) after a 14-day-repeated administration of meclizine (12.5 mg) were 167 (83\u2013250) ng\/mL, 3.7 (3.1\u20134.2) h, 1170 (765\u20131570) ng\u00b7h\/mL, and 7.4 (6.7\u20138.0) h, respectively. The AUC<jats:sub>0-6h<\/jats:sub> after the final administration was 1.5 times that after the initial dose. C<jats:sub>max<\/jats:sub> and AUC were higher in cohort 2 than in cohort 1 in a dose-dependent manner. Regarding the regimen of meclizine 12.5 and 25 mg in patients &lt; 20 kg and \u2265 20 kg, respectively, the average (95% CI) AUC<jats:sub>0-24h<\/jats:sub> was 1270 (1100\u20131440) ng\u00b7h\/mL. Compartment models demonstrated that the plasma concentration of meclizine achieved at a steady state after the 14th administration. Long-term administration of meclizine 12.5 or 25 mg\/day is recommended for phase 2 clinical trials in children with ACH.<\/jats:p>","DOI":"10.1371\/journal.pone.0283425","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T17:44:58Z","timestamp":1689011098000},"page":"e0283425","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Phase 1b study on the repurposing of meclizine hydrochloride for children with achondroplasia"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4540-1556","authenticated-orcid":true,"given":"Masaki","family":"Matsushita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kitoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3350-1664","authenticated-orcid":true,"given":"Kenichi","family":"Mishima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunari","family":"Kamiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisaku","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genta","family":"Takemoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Sawamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nakai","family":"Yasuhiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Nishida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiro","family":"Imagama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,7,10]]},"reference":[{"issue":"2","key":"pone.0283425.ref001","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/0092-8674(94)90302-6","article-title":"Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia","volume":"78","author":"R Shiang","year":"1994","journal-title":"Cell"},{"issue":"6494","key":"pone.0283425.ref002","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/371252a0","article-title":"Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia","volume":"371","author":"F Rousseau","year":"1994","journal-title":"Nature"},{"issue":"7","key":"pone.0283425.ref003","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1007\/s00431-017-2923-y","article-title":"Final adult height in long-term growth hormone-treated achondroplasia patients","volume":"176","author":"D Harada","year":"2017","journal-title":"Eur J Pediatr"},{"issue":"9","key":"pone.0283425.ref004","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1302\/0301-620X.96B9.33840","article-title":"Early and late fracture following extensive limb lengthening in patients with achondroplasia and hypochondroplasia","volume":"96-B","author":"H Kitoh","year":"2014","journal-title":"Bone Joint J"},{"issue":"1","key":"pone.0283425.ref005","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1056\/NEJMoa1813446","article-title":"C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia","volume":"381","author":"R Savarirayan","year":"2019","journal-title":"N Engl J Med"},{"issue":"10252","key":"pone.0283425.ref006","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/S0140-6736(20)31541-5","article-title":"Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial","volume":"396","author":"R Savarirayan","year":"2020","journal-title":"Lancet"},{"issue":"12","key":"pone.0283425.ref007","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1038\/s41436-021-01287-7","article-title":"Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study","volume":"23","author":"R Savarirayan","year":"2021","journal-title":"Genet Med"},{"issue":"203","key":"pone.0283425.ref008","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3006247","article-title":"Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice","volume":"5","author":"S Garcia","year":"2013","journal-title":"Sci Transl Med"},{"issue":"12","key":"pone.0283425.ref009","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0244368","article-title":"In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as treatment for achondroplasia","volume":"15","author":"D Goncalves","year":"2020","journal-title":"PLoS One"},{"issue":"5","key":"pone.0283425.ref010","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1172\/JCI83926","article-title":"Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model","volume":"126","author":"D Komla-Ebri","year":"2016","journal-title":"J Clin Invest"},{"issue":"592","key":"pone.0283425.ref011","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aba4226","article-title":"An RNA aptamer restores defective bone growth in FGFR3-related skeletal dysplasia in mice","volume":"13","author":"T Kimura","year":"2021","journal-title":"Sci Transl Med"},{"issue":"12","key":"pone.0283425.ref012","doi-asserted-by":"crossref","first-page":"e81569","DOI":"10.1371\/journal.pone.0081569","article-title":"Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia","volume":"8","author":"M Matsushita","year":"2013","journal-title":"PLoS One"},{"issue":"1","key":"pone.0283425.ref013","doi-asserted-by":"crossref","first-page":"7371","DOI":"10.1038\/s41598-017-07044-8","article-title":"Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia","volume":"7","author":"M Matsushita","year":"2017","journal-title":"Sci Rep"},{"issue":"9","key":"pone.0283425.ref014","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1177\/0091270011414575","article-title":"Meclizine metabolism and pharmacokinetics: formulation on its absorption","volume":"52","author":"Z Wang","year":"2012","journal-title":"J Clin Pharmacol"},{"issue":"4","key":"pone.0283425.ref015","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0229639","article-title":"Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia","volume":"15","author":"H Kitoh","year":"2020","journal-title":"PLoS One"},{"issue":"5","key":"pone.0283425.ref016","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s00228-016-2012-6","article-title":"Treatment of nausea and vomiting during pregnancy -a cross-sectional study among 712 Norwegian women","volume":"72","author":"K Heitmann","year":"2016","journal-title":"Eur J Clin Pharmacol"},{"issue":"1","key":"pone.0283425.ref017","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1080\/02813432.2019.1569424","article-title":"Women\u2019s perspectives on the management and consequences of hyperemesis gravidarum\u2014a descriptive interview study","volume":"37","author":"GC Havnen","year":"2019","journal-title":"Scand J Prim Health Care"},{"issue":"4","key":"pone.0283425.ref018","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/0002-9378(65)90515-6","article-title":"Evaluation of the teratogenic effect of meclizine in man","volume":"93","author":"J Yerushalmy","year":"1965","journal-title":"Am J Obstet Gynecol"},{"issue":"12","key":"pone.0283425.ref019","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1007\/s00228-005-0055-1","article-title":"Use of antiemetic drugs during pregnancy in Sweden","volume":"61","author":"C Asker","year":"2005","journal-title":"Eur J Clin Pharmacol"},{"issue":"6","key":"pone.0283425.ref020","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1097\/00004703-198812000-00008","article-title":"The failure of antimotion sickness medication to improve reading in developmental dyslexia: results of a randomized trial","volume":"9","author":"JE Fagan","year":"1988","journal-title":"J Dev Behav Pediatr"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0283425","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T11:38:44Z","timestamp":1728905924000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0283425"}},"subtitle":[],"editor":[{"given":"Yann","family":"Ben\u00e9treau-Dupin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,7,10]]},"references-count":20,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0283425","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,10]]}}}