Population Pharmacodynamics of Vamicamide, a New Anticholinergic Drug, Analyzed by Nonlinear Mixed Effect Modeling: Relationship between the Average Urine Flow Rate and Serum Concentration in Healthy Volunteers

Masato Terakawa, Nami Iyota, Yusuke Tanigawara

Research output: Contribution to journalArticle

Abstract

The population pharmacodynamics of vamicamide, a new anticholinergic drug, Were analyzed by nonlinear mixed effect modeling (NONMEM) in 16 healthy male subjects. The subjects were given orally 18, 36 or 48 mg of vamicamide in a single- or multiple-dose regimen. Serum concentrations of vamicamide were measured frequently; the average urine flow rates (AFRs), estimated simply by dividing the urine volume by the time during voiding, were measured on each occasion of urination. Serum concentrations corresponding to the time of urination were predicted by curve-fitting the individual data (a total of 293 serum data) to a one-compartment model with first-order absorption. The serum concentration-AFR data (381 data pairs) thus obtained were used for NONMEM analysis. The Emax model with baseline controls was used for serum concentration-AFR response data. The voided volume significantly affected not only the baseline AFR but also maximum response (Emax). However, the concentration which causes half of Emax (EC50) Was independent of voided volume and was estimated to be 167 ng/ml. At the serum concentration of 140 ng/ml, which is the maximum serum concentration at therapeutic standard dosage regimen, the percent reduction of AFR from the baseline value was estimated to be 32 and 38% when the voided volume is assumed to be 100 and 400 ml, respectively. Despite the wide range of variability in AFR, the NONMEM analysis provided clinically significant concentration-response curves. This population approach appears recommendable for further clinical applications.

Original languageEnglish
Pages (from-to)603-613
Number of pages11
JournalJapanese Journal of Clinical Pharmacology and Therapeutics
Volume25
Issue number4
DOIs
Publication statusPublished - 1994

Keywords

  • NONMEM
  • anticholinergic drug
  • average urine flow rate
  • population pharmacodynamics
  • vamicamide

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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