Journal Article

Phase 1b study on the repurposing of meclizine hydrochloride for children with achondroplasia

Kato, Daisaku, Sawamura, Kenta, Takemoto, Genta, Nishida, Kazuki, Yasuhiro, Nakai, Kitoh, Hiroshi, Imagama, Shiro, Ueno, Shinji, Matsushita, Masaki, Kamiya, Yasunari, Mishima, Kenichi

2023

Overview

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 5–10 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 max ), peak drug concentration (T max ), area under the curve (AUC) from 0 to 24 h, and terminal elimination half-life (t 1/2 ) after a 14-day-repeated administration of meclizine (12.5 mg) were 167 (83–250) ng/mL, 3.7 (3.1–4.2) h, 1170 (765–1570) ng·h/mL, and 7.4 (6.7–8.0) h, respectively. The AUC 0-6h after the final administration was 1.5 times that after the initial dose. C max 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 < 20 kg and ≥ 20 kg, respectively, the average (95% CI) AUC 0-24h was 1270 (1100–1440) ng·h/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.

• Publisher: Public Library of Science
• Subject: Achondroplasia / Achondroplasia - genetics / Analysis / Animal models / Animals / Anticoagulants / Area Under Curve / Biology and Life Sciences / Bone Development / Bone dysplasia / Bone growth / Care and treatment / Children / Clinical trials / Diagnosis / Dosage and administration / Drug discovery / Drug dosages / Drug Repositioning / Electrocardiography / Fibroblast growth factor receptor 3 / Fibroblast growth factor receptors / Fibroblast growth factors / Growth factors / Health aspects / Hospitals / Laboratories / Meclizine / Medicine and Health Sciences / Methods / Mice / Microscopy / Motion sickness / Mutation / Nonprescription drugs / Pediatrics / Pharmaceuticals / Pharmacokinetics / Prescription drugs / Product development / Research and Analysis Methods / Skeleton / Steady state