Population Pharmacokinetic Model of the Pregabalin-Sildenafil Interaction in Rats: Application of Simulation to Preclinical PK-PD Study Design
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.
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.
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.
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.
- Population Pharmacokinetic Model of the Pregabalin-Sildenafil Interaction in Rats: Application of Simulation to Preclinical PK-PD Study Design
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Volume 26, Issue 10 , pp 2259-2269
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
- Additional Links
- neuropathic pain
- optimal sampling
- synergistic interaction
- trial simulation
- Industry Sectors
- Author Affiliations
- 1. Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands
- 2. Pfizer, Global Research & Development, Sandwich, United Kingdom
- 3. University of Pittsburgh, Pennsylvania, USA
- 4. LAP&P Consultants BV, Leiden, The Netherlands