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

Bender G, Gosset J, Florian J, Tan K, Field M, Marshall S, DeJongh J, Bies R, Danhof M - Pharm. Res. (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.

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.

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Related in: MedlinePlus

Posterior predictive check of pregabalin concentration vs. time profiles for each of the treatment groups administered a 2-hr pregabalin infusion at: A 4 mg/kg/hr without sildenafil, B 10 mg/kg/hr without sildenafil, C 4 mg/kg/hr with sildenafil, and D 10 mg/kg/hr with sildenafil. Lines represent the 90% prediction interval for the model.
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Fig5: Posterior predictive check of pregabalin concentration vs. time profiles for each of the treatment groups administered a 2-hr pregabalin infusion at: A 4 mg/kg/hr without sildenafil, B 10 mg/kg/hr without sildenafil, C 4 mg/kg/hr with sildenafil, and D 10 mg/kg/hr with sildenafil. Lines represent the 90% prediction interval for the model.

Mentions: Final parameter values for this model are listed in Table IV. Bootstrapping with replacement demonstrated a good model fit, mean parameter values remained near the final model, and CV% was low. A posterior predictive check also demonstrated a good model fit. Fig. 5 demonstrates that most of the observed data points fall within the 90% prediction interval.Fig. 5


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

Bender G, Gosset J, Florian J, Tan K, Field M, Marshall S, DeJongh J, Bies R, Danhof M - Pharm. Res. (2009)

Posterior predictive check of pregabalin concentration vs. time profiles for each of the treatment groups administered a 2-hr pregabalin infusion at: A 4 mg/kg/hr without sildenafil, B 10 mg/kg/hr without sildenafil, C 4 mg/kg/hr with sildenafil, and D 10 mg/kg/hr with sildenafil. Lines represent the 90% prediction interval for the model.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2737110&req=5

Fig5: Posterior predictive check of pregabalin concentration vs. time profiles for each of the treatment groups administered a 2-hr pregabalin infusion at: A 4 mg/kg/hr without sildenafil, B 10 mg/kg/hr without sildenafil, C 4 mg/kg/hr with sildenafil, and D 10 mg/kg/hr with sildenafil. Lines represent the 90% prediction interval for the model.
Mentions: Final parameter values for this model are listed in Table IV. Bootstrapping with replacement demonstrated a good model fit, mean parameter values remained near the final model, and CV% was low. A posterior predictive check also demonstrated a good model fit. Fig. 5 demonstrates that most of the observed data points fall within the 90% prediction interval.Fig. 5

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus