PMID- 37428729
OWN - NLM
STAT- MEDLINE
DCOM- 20230712
LR  - 20230718
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 18
IP  - 7
DP  - 2023
TI  - Phase 1b study on the repurposing of meclizine hydrochloride for children with 
      achondroplasia.
PG  - e0283425
LID - 10.1371/journal.pone.0283425 [doi]
LID - e0283425
AB  - 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 (Cmax), peak drug 
      concentration (Tmax), area under the curve (AUC) from 0 to 24 h, and terminal 
      elimination half-life (t1/2) 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 AUC0-6h after the final administration was 1.5 
      times that after the initial dose. Cmax 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) 
      AUC0-24h 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.
CI  - Copyright: (c) 2023 Matsushita et al. This is an open access article distributed 
      under the terms of the Creative Commons Attribution License, which permits 
      unrestricted use, distribution, and reproduction in any medium, provided the 
      original author and source are credited.
FAU - Matsushita, Masaki
AU  - Matsushita M
AUID- ORCID: 0000-0003-4540-1556
AD  - Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
FAU - Kitoh, Hiroshi
AU  - Kitoh H
AD  - Department of Orthopaedic Surgery, Aichi Children's Health and Medical Center, 
      Obu, Japan.
AD  - Department of Comprehensive Pediatric Medicine, Nagoya University Graduate School 
      of Medicine, Nagoya, Japan.
FAU - Mishima, Kenichi
AU  - Mishima K
AUID- ORCID: 0000-0003-3350-1664
AD  - Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
FAU - Kamiya, Yasunari
AU  - Kamiya Y
AD  - Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
FAU - Kato, Daisaku
AU  - Kato D
AD  - Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
FAU - Takemoto, Genta
AU  - Takemoto G
AD  - Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
FAU - Sawamura, Kenta
AU  - Sawamura K
AD  - Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
AD  - Department of Orthopaedic Surgery, Aichi Children's Health and Medical Center, 
      Obu, Japan.
FAU - Ueno, Shinji
AU  - Ueno S
AD  - Department of Ophthalmology, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
AD  - Department of Ophthalmology, Hirosaki University Graduate School of Medicine, 
      Hirosaki, Japan.
FAU - Yasuhiro, Nakai
AU  - Yasuhiro N
AD  - Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan.
FAU - Nishida, Kazuki
AU  - Nishida K
AD  - Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan.
FAU - Imagama, Shiro
AU  - Imagama S
AD  - Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230710
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 3L5TQ84570 (Meclizine)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Meclizine
MH  - Drug Repositioning
MH  - *Achondroplasia/genetics
MH  - Area Under Curve
MH  - Bone Development
PMC - PMC10332602
COIS- The authors have declared that no competing interests exist.
EDAT- 2023/07/10 19:08
MHDA- 2023/07/12 06:42
PMCR- 2023/07/10
CRDT- 2023/07/10 13:33
PHST- 2022/04/25 00:00 [received]
PHST- 2023/02/01 00:00 [accepted]
PHST- 2023/07/12 06:42 [medline]
PHST- 2023/07/10 19:08 [pubmed]
PHST- 2023/07/10 13:33 [entrez]
PHST- 2023/07/10 00:00 [pmc-release]
AID - PONE-D-22-10628 [pii]
AID - 10.1371/journal.pone.0283425 [doi]
PST - epublish
SO  - PLoS One. 2023 Jul 10;18(7):e0283425. doi: 10.1371/journal.pone.0283425. 
      eCollection 2023.