Population pharmacokinetic model of the pregabalin-sildenafil interaction in rats: Application of simulation to preclinical PK-PD study design

Gregor Bender, James Gosset, Jeff Florian, Keith Tan, Mark Field, Scott Marshall, Joost Dejongh, Robert Bies, Meindert Danhof

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Purpose: Preliminary evidence has suggested a synergistic interaction between pregabalin and sildenafil for the treatment of neuropathic pain. The focus of this study was to determine the influence of sildenafil on the pharmacokinetics (PK) of pregabalin with the objective of informing the design of a quantitative pharmacodynamic (PD) study. Methods: The pharmacokinetics were determined in rats following 2-hr intravenous infusions of pregabalin at doses of 4 mg/kg/hr and 10 mg/kg/hr with and without a sildenafil bolus (2.2 mg) and steady state infusion (12 mg/kg/hr for 6 h). This PK model was utilized in a preclinical trial simulation with the aim of selecting the optimal sampling strategy to characterize the PK-PD profile in a future study. Eight logistically feasible PK sampling strategies were simulated in NONMEM and examined through trial simulation techniques. Results: A two-compartment population PK model best described pregabalin pharmacokinetics. Significant model covariates included either a binary effect of sildenafil administration (30.2% decrease in clearance) or a concentration-dependent effect due to sildenafil's active metabolite. Conclusions: Analysis of simulations indicated that three post-PD samples had the best cost/benefit ratio by providing a significant increase in the precision (and minor improvement in bias) of both PK and PD parameters compared with no PK sampling.

Original languageEnglish (US)
Pages (from-to)2259-2269
Number of pages11
JournalPharmaceutical Research
Volume26
Issue number10
DOIs
StatePublished - Oct 1 2009
Externally publishedYes

Keywords

  • Neuropathic pain
  • Optimal sampling
  • Synergistic interaction
  • Trial simulation

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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