Population Pharmacokinetic Model of the Pregabalin-Sildenafil Interaction in Rats: Application of Simulation to Preclinical PK-PD Study Design

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.

Pharmacokinetic–Pharmacodynamic Analysis of the Static Allodynia Response to Pregabalin and Sildenafil in a Rat Model of Neuropathic Pain

“…After blood sampling, samples were centrifuged at 3000 rpm for 3 min, and plasma was separated and then stored at Ϫ20°C until analysis. PK sampling was determined by a preclinical trial simulation as described previously (Bender et al, 2009). Based on these simulations, three PK samples were obtained at 6, 8, and 24 h after the PD experiment.…”

“…The final model describes the influence of fixed effects (i.e., demographic factors) on the PK and PD parameters (Ette et al, 1995a,b). The population PK model used for this analysis was reported by Bender et al (2009).…”

“…A two-compartment model based on previous analysis (Bender et al, 2009) was used as the structural model to describe the concentration time course of pregabalin. Although previous results demonstrated that the numerically superior PK model used a continuous covariate for the sildenafil metabolite, similar parameters were obtained if either a continuous sildenafil concentration or binary representation for sildenafil presence/absence was incorporated during the analysis.…”

“…The final model structure was developed by testing the effect of the following subject-specific covariates: 1) body weight; 2) age; 3) time after surgery; 4) time after catheterization surgery; 5) sildenafil concentration; and 6) sildenafil metabolite concentration. Sildenafil metabolite concentration was included as a covariate for thoroughness as it was identified previously as a significant PK model covariate when included as a continuous measure (Bender et al, 2009). All of the above covariates were initially modeled as continuous.…”

“…An optimal post-PD sampling schedule developed previously was used to allow for accurate identification of individual rat PK while not interfering with PD measurements taken during the initial 6 h of the experiment (Field and Williams, 2008;Bender et al, 2009). These data then served as the basis for developing a population PK-PD model to quantify the static allodynia response to pregabalin alone and then examine the influence of concomitant sildenafil on this response.…”