Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia

Abstract

Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We identified that meclizine hydrochloride inhibited FGFR3 signaling in various chondrocytic cells and promoted longitudinal bone growth in mouse model of ACH. Meclizine has safely been used for more than 50 years, but it lacks the safety data for repeated administration and pharmacokinetics (PK) when administered to children. We performed a phase Ia study to evaluate the PK and safety of meclizine administered orally to ACH children. Twelve ACH children aged from 5 to younger than 11 years were recruited, and the first 6 subjects received once a day of meclizine in the fasted condition, subsequent 6 subjects received twice a day of meclizine in the fed condition. Meclizine was well tolerated in ACH children with no serious adverse events. The mean C max , T max , AUC 0-24h , t1/2 during 24 hours in the fasted condition were 130 ng/mL, 1.7 hours, 761 ng�h/mL, and 8.5 hours respectively. The simulation of repeated administration of meclizine for 14 days demonstrated that plasma concentration apparently reached steady state around 10 days after the first dose both at once a day and twice a day administration. The AUC 0-10h of the fasting and fed condition were 504 ng�h/mL and 813 ng�h/mL, respectively, indicating exposure of meclizine increased with the diet. Although higher drug exposure was confirmed in ACH children compared to adults, a single administration of meclizine seemed to be well tolerated.

Long-term oral meclozine administration improves survival rate and spinal canal stenosis during postnatal growth in a mouse model of achondroplasia in both sexes

“… 39 Further research with ASP5878 is needed before it can be applied in clinical settings. In contrast, meclozine has been used in children for anti-motion sickness for more than 50 yr. 40 There were no reports of severe adverse events after repeated doses of meclozine (25 mg/d) for 3 mo in patients with developmental dyslexia aged 9–14 yr. 41 In our previous pharmacokinetic analyses, 16 the peak drug concentration (C max ) and area under the concentration-time curve of 2 mg/kg meclozine in mice were lower than those obtained with 25 mg/kg/d in adult humans, 42 which is the dose used for the treatment of motion sickness. Therefore, long-term administration of 25 mg/kg/d or less of meclozine is likely to be a clinically attainable dose for promoting bone growth in pediatric patients with ACH.…”

Burden and Treatment of Achondroplasia: A Systematic Literature Review

“…In a phase 1a safety study on meclizine, no serious AEs were reported. Four out of six children experienced a low-grade AE in the group receiving one 25 mg tablet per day in the fasted state, while one out of six children experienced a low-grade AE in the group receiving two 25 mg tablets per day in the fed state [ 92 ]. As this study was only conducted over a 7-day period, longer follow-up would be needed to evaluate the reliability of this finding.…”

Meclozine ameliorates bone mineralization and growth plate structure in a mouse model of X‑linked hypophosphatemia

“…Additionally, some children fear the burosumab administration via injection, while oral administration of sodium phosphate does not always achieve the correct dosage due to increased renal phosphate wasting ( 22 ). We previously demonstrated that meclozine suppressed the short-statured phenotype of achondroplasia mice by attenuating FGFR3 signaling ( 12 , 13 , 23 ), and clinical trials of meclozine in children with achondroplasia are under way ( 24 ). To the best of our knowledge, current study demonstrated the first evidence of the effect of meclozine on improving bone mineralization in a mouse model of XLH.…”