Population pharmacokinetic model of the pregabalin-sildenafil interaction in rats: application of simulation to preclinical PK-PD study design.
OBJECTIVE
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.
Bender
Gregor
G
Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
Gosset
James
J
Florian
Jeff
J
Tan
Keith
K
Field
Mark
M
Marshall
Scott
S
DeJongh
Joost
J
Bies
Robert
R
Danhof
Meindert
M
D000818:Animals; D003198:Computer Simulation; D018592:Cross-Over Studies; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions / Q000502:physiology; D008297:Male; D008954:Models, Biological; D010879:Piperazines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000069583:Pregabalin; D011687:Purines / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000068677:Sildenafil Citrate