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Population pharmacokinetic model of the pregabalin-sildenafil interaction in rats: application of simulation to preclinical PK-PD study design.
Bender, Gregor; Gosset, James; Florian, Jeff; Tan, Keith; Field, Mark; Marshall, Scott; DeJongh, Joost; Bies, Robert; Danhof, Meindert.
  • Bender G; Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
Pharm Res ; 26(10): 2259-69, 2009 Oct.
Article en En | MEDLINE | ID: mdl-19669867
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.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Piperazinas / Sulfonas / Simulación por Computador / Ácido gamma-Aminobutírico / Modelos Biológicos Límite: Animals Idioma: En Año: 2009 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Piperazinas / Sulfonas / Simulación por Computador / Ácido gamma-Aminobutírico / Modelos Biológicos Límite: Animals Idioma: En Año: 2009 Tipo del documento: Article