Pharmaceutical Research

, Volume 18, Issue 8, pp 1210–1219

Modeling and Simulation for Clinical Trial Design Involving a Categorical Response: A Phase II Case Study with Naratriptan

  • Ivan Nestorov
  • Gordon Graham
  • Stephen Duffull
  • Leon Aarons
  • Eliane Fuseau
  • Peter Coates
Article

DOI: 10.1023/A:1010943430471

Cite this article as:
Nestorov, I., Graham, G., Duffull, S. et al. Pharm Res (2001) 18: 1210. doi:10.1023/A:1010943430471

Abstract

Purpose. The overall aim of the present study was to investigate retrospectively the feasibility and utility of model-based clinical trial simulation as applied to the clinical development of naratriptan with effect measured on a categorical scale.

Methods. A PK-PD model for naratriptan was developed by using information gathered from previous naratriptan and sumatriptan preclinical and clinical trials. The phase IIa naratriptan data were used to check the PK-PD model in its ability to describe future data. A further PK-PD model was developed by using the phase IIa naratriptan data, and a phase IIb trial was designed by simulation with the use of Matlab. The design resulting from clinical trial simulation was compared with that derived by using D-optimal design.

Results. The PK-PD model showed reasonable agreement with the data observed in the phase IIa naratriptan clinical trial. Clinical trial simulation resulted in a design with four or five arms at 0 mg, 2.5 and/or 5 mg, 10 mg, and 20 mg, PD measurements to be taken at 0, 2, and 4 or 6 h and at least 150 patients per arm. A sub-D-optimal design resulted in two dosing arms at 0 and 10 mg and PD measurements to be taken at 1 and 2 h.

Conclusions. Clinical trial simulation is a useful tool for the quantitative assessment of the influence of the controllable factors and is the only tool for the quantitative assessment of the uncontrollable factors on the power of a clinical trial.

simulation design clinical trials naratriptan pharmacokinetics pharmacodynamics 

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Ivan Nestorov
    • 1
  • Gordon Graham
    • 1
  • Stephen Duffull
    • 2
  • Leon Aarons
    • 3
  • Eliane Fuseau
    • 4
  • Peter Coates
    • 4
  1. 1.Centre for Applied Pharmacokinetic ResearchManchester UniversityManchesterUnited Kingdom
  2. 2.School of PharmacyUniversity of QueenslandBrisbaneAustralia
  3. 3.School of PharmacyManchester UniversityManchesterUnited Kingdom
  4. 4.Clinical PharmacologyGlaxo Wellcome Research and Development Ltd.Greenford, MiddlesexUnited Kingdom

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