Population Pharmacokinetic Analysis of Zolmitriptan and Its Metabolite in Adults and Adolescents to Support Dose Selection in Children With Migraine

• Published in: Journal of clinical pharmacology Vol. 57; no. 10; p. 1258
• Main Authors: Zhou, Wangda, Li, Jianguo, Birmingham, Bruce, Xu, Hongmei, Lillieborg, Stefan, Zhou, Diansong, Al-Huniti, Nidal
• Format: Journal Article
• Language: English
• Published: England 01.10.2017
• Subjects: Administration, Intranasal; Adolescent; Adult; Body Weight; Child; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Migraine Disorders - blood; Migraine Disorders - drug therapy; Migraine Disorders - metabolism; Models, Biological; Oxazoles - blood; Oxazolidinones - administration & dosage; Oxazolidinones - blood; Oxazolidinones - pharmacokinetics; Oxazolidinones - therapeutic use; Serotonin 5-HT1 Receptor Agonists - administration & dosage; Serotonin 5-HT1 Receptor Agonists - blood; Serotonin 5-HT1 Receptor Agonists - pharmacokinetics; Serotonin 5-HT1 Receptor Agonists - therapeutic use; Tryptamines - administration & dosage; Tryptamines - blood; Tryptamines - pharmacokinetics; Tryptamines - therapeutic use; Young Adult; zolmitriptan nasal spray (ZNS); zolmitriptan; parent metabolite; pediatrics; population pharmacokinetics
• DOI: 10.1002/jcph.935

Zolmitriptan is a serotonin (5-HT) receptor agonist effective for the treatment of migraine. This analysis aimed to develop a population pharmacokinetic (PK) model for zolmitriptan and its active metabolite in adults and adolescents and provide appropriate dosing regimens to be used in clinical trials for children 6-11 years old. The data from a single-dose clinical study of 5.0-mg zolmitriptan nasal spray (ZNS) conducted in adult and adolescent patients with migraine between migraine attacks was applied. Similar plasma concentration profiles of zolmitriptan and its metabolite, 183C91, were observed in adults and adolescents. A 1-compartment model with first-order absorption and first-order elimination reasonably described the zolmitriptan PK. With a portion of elimination of zolmitriptan being treated as the conversion from zolmitriptan to 183C91, the disposition of 183C91 was described by a 1-compartment model with first-order elimination. The estimated typical apparent volume of distribution and clearance of zolmitriptan were 136 L and 121 L/h, respectively, with 56.5% and 42.6% between-subject variability, respectively. Based on the simulation results with the final population PK model, a body weight-based dosing scheme of 5.0 and 2.5 mg ZNS in children greater than and less than 50 kg is recommended to achieve exposures similar to those of the adult and adolescent population administered 5.0 mg ZNS. The recommended doses for children to achieve exposure similar to that observed in adults given 2.5 mg ZNS are 2.5 mg (≥50 kg) and 1.0 mg (15-50 kg). These dosing regimens could be used in future clinical trials.