Pharmacokinetics and Tolerability of Rizatriptan in Pediatric Migraineurs in a Randomized Study

Authors

  • Iain P. Fraser MD, DPhil,

    Corresponding author
    1. From Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA (I.P. Fraser, L. Han, T.H. Han, C-C. Li, D. Hreniuk, S.A. Stoch, and J.A. Wagner); Dallas Pediatric Neurology, Dallas, TX, USA (S. Linder); Premiere Research Institute, West Palm Beach, FL, USA (P. Winner).
      I.P. Fraser, Merck Sharp & Dohme Corp., 126 E. Lincoln Avenue, PO Box 2000, Rahway, NJ 07065-0900, USA, email: iain_fraser@merck.com
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  • Lingling Han PhD,

    1. From Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA (I.P. Fraser, L. Han, T.H. Han, C-C. Li, D. Hreniuk, S.A. Stoch, and J.A. Wagner); Dallas Pediatric Neurology, Dallas, TX, USA (S. Linder); Premiere Research Institute, West Palm Beach, FL, USA (P. Winner).
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  • Tae H. Han PhD,

    1. From Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA (I.P. Fraser, L. Han, T.H. Han, C-C. Li, D. Hreniuk, S.A. Stoch, and J.A. Wagner); Dallas Pediatric Neurology, Dallas, TX, USA (S. Linder); Premiere Research Institute, West Palm Beach, FL, USA (P. Winner).
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  • Chi-Chung Li PhD,

    1. From Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA (I.P. Fraser, L. Han, T.H. Han, C-C. Li, D. Hreniuk, S.A. Stoch, and J.A. Wagner); Dallas Pediatric Neurology, Dallas, TX, USA (S. Linder); Premiere Research Institute, West Palm Beach, FL, USA (P. Winner).
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  • David Hreniuk BS,

    1. From Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA (I.P. Fraser, L. Han, T.H. Han, C-C. Li, D. Hreniuk, S.A. Stoch, and J.A. Wagner); Dallas Pediatric Neurology, Dallas, TX, USA (S. Linder); Premiere Research Institute, West Palm Beach, FL, USA (P. Winner).
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  • S. Aubrey Stoch MD,

    1. From Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA (I.P. Fraser, L. Han, T.H. Han, C-C. Li, D. Hreniuk, S.A. Stoch, and J.A. Wagner); Dallas Pediatric Neurology, Dallas, TX, USA (S. Linder); Premiere Research Institute, West Palm Beach, FL, USA (P. Winner).
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  • John A. Wagner MD, PhD,

    1. From Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA (I.P. Fraser, L. Han, T.H. Han, C-C. Li, D. Hreniuk, S.A. Stoch, and J.A. Wagner); Dallas Pediatric Neurology, Dallas, TX, USA (S. Linder); Premiere Research Institute, West Palm Beach, FL, USA (P. Winner).
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  • Steven Linder MD,

    1. From Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA (I.P. Fraser, L. Han, T.H. Han, C-C. Li, D. Hreniuk, S.A. Stoch, and J.A. Wagner); Dallas Pediatric Neurology, Dallas, TX, USA (S. Linder); Premiere Research Institute, West Palm Beach, FL, USA (P. Winner).
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  • Paul Winner DO

    1. From Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA (I.P. Fraser, L. Han, T.H. Han, C-C. Li, D. Hreniuk, S.A. Stoch, and J.A. Wagner); Dallas Pediatric Neurology, Dallas, TX, USA (S. Linder); Premiere Research Institute, West Palm Beach, FL, USA (P. Winner).
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  • Conflict of Interest: This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. The funding organization was involved in the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. Iain P. Fraser, Lingling Han, Tae H. Han, Chi-Chung Li, David Hreniuk, S. Aubrey Stoch, and John A. Wagner are or were employees of Merck and own or owned stock/stock options in Merck. Steven Linder and Paul Winner have received research funding from Merck.

  • Current affiliation of Tae H. Han: Seattle Genetics, Bothell, WA, USA.

  • Clinical Trial Registration Number (in clinicaltrials.gov): NCT00604812.

I.P. Fraser, Merck Sharp & Dohme Corp., 126 E. Lincoln Avenue, PO Box 2000, Rahway, NJ 07065-0900, USA, email: iain_fraser@merck.com

Abstract

Objective.— To evaluate the pharmacokinetic profile and tolerability of single doses of rizatriptan oral disintegrating tablets (ODTs) in pediatric migraineurs.

Background.— Acute migraine treatment options for children are limited despite a rising migraine prevalence. No triptans are approved in those under 12, and only sumatriptan nasal spray (European Union) and almotriptan tablets (USA) are approved for those aged 12-17. Appropriate dose selection based on body weight may be a factor in establishing treatment efficacy in this population.

Methods.— Randomized, double-blind, placebo-controlled, parallel group, single-dose study in 6- to 17-year-old migraineurs. The study was performed between acute migraine attacks. Subjects were allocated to 1 of 2 groups based on body weight: (1) those weighing <40 kg received rizatriptan ODT 5 mg or placebo; (2) those weighing ≥40 kg received rizatriptan 10 mg ODT or placebo. Pharmacokinetic data were compared with historical data on rizatriptan ODT 10 mg in healthy adults.

Results.— The geometric mean area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)) (hours·ng/mL) and maximum peak plasma concentration (Cmax) (ng/mL) were 56.68 (95% confidence interval [CI]: 48.60, 66.09) and 22.39 (95% CI: 17.90, 28.02), respectively, for the <40 kg group and 78.49 (95% CI: 68.93, 89.38) and 22.27 (95% CI: 18.43, 26.92), respectively, for the ≥40 kg group. For the comparison of children vs adults, the geometric mean ratios for rizatriptan AUC(0-∞) and Cmax were 0.85 (90% CI: 0.73, 0.98) and 1.07 (90% CI: 0.86, 1.34), respectively, for the <40 kg group vs historical adult data and 1.17 (90% CI: 1.02, 1.34) and 1.06 (90% CI: 0.87, 1.30), respectively, for the ≥40 kg group vs historical adult data. There were no serious adverse events, and rizatriptan was generally well tolerated.

Conclusions.— In pediatric migraineurs, a weight-based dosing scheme generated plasma rizatriptan AUC(0-∞) and Cmax values that were generally similar to those historically observed in adults administered a 10-mg dose of rizatriptan ODT (a proven effective dose). The data support further evaluation of the safety, tolerability, and efficacy of this rizatriptan dosing scheme in larger scale clinical trials in the pediatric migraineur population.

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