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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

Diagnostic plots for the pregabalin PK model: A observed vs. individual predicted, B observed vs. population predicted, C weighted residuals vs. time, D and weighted residuals vs. predicted pregabalin concentration. Symbols depict data points from rats administered 4 mg/kg without sildenafil (circles), 10 mg/kg without sildenafil (squares), 4 mg/kg with sildenafil (+), and 10 mg/kg with sildenafil (triangles).
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Fig3: Diagnostic plots for the pregabalin PK model: A observed vs. individual predicted, B observed vs. population predicted, C weighted residuals vs. time, D and weighted residuals vs. predicted pregabalin concentration. Symbols depict data points from rats administered 4 mg/kg without sildenafil (circles), 10 mg/kg without sildenafil (squares), 4 mg/kg with sildenafil (+), and 10 mg/kg with sildenafil (triangles).

Mentions: A two-compartment model was chosen as the final structural model to describe the concentration time course of pregabalin. Estimated model parameters are listed in Table IV. Both between-subject variability and between-occasion variability were determined in the base model for clearance (BSV 0.024(24.7%), BOV 0.098(27.1%)) and the volume of the central compartment (BSV 0.017(9.4%), BOV 0.015(9.0%)). A proportional error model was selected to account for the residual variability. Overall diagnostic plots demonstrated a good model fit (Fig. 3). Observed values versus both population and individual predicted were near the line of identity. Weighted residuals were relatively small in magnitude and randomly distributed when viewed versus time and concentration.Table IV


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)

Diagnostic plots for the pregabalin PK model: A observed vs. individual predicted, B observed vs. population predicted, C weighted residuals vs. time, D and weighted residuals vs. predicted pregabalin concentration. Symbols depict data points from rats administered 4 mg/kg without sildenafil (circles), 10 mg/kg without sildenafil (squares), 4 mg/kg with sildenafil (+), and 10 mg/kg with sildenafil (triangles).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2737110&req=5

Fig3: Diagnostic plots for the pregabalin PK model: A observed vs. individual predicted, B observed vs. population predicted, C weighted residuals vs. time, D and weighted residuals vs. predicted pregabalin concentration. Symbols depict data points from rats administered 4 mg/kg without sildenafil (circles), 10 mg/kg without sildenafil (squares), 4 mg/kg with sildenafil (+), and 10 mg/kg with sildenafil (triangles).
Mentions: A two-compartment model was chosen as the final structural model to describe the concentration time course of pregabalin. Estimated model parameters are listed in Table IV. Both between-subject variability and between-occasion variability were determined in the base model for clearance (BSV 0.024(24.7%), BOV 0.098(27.1%)) and the volume of the central compartment (BSV 0.017(9.4%), BOV 0.015(9.0%)). A proportional error model was selected to account for the residual variability. Overall diagnostic plots demonstrated a good model fit (Fig. 3). Observed values versus both population and individual predicted were near the line of identity. Weighted residuals were relatively small in magnitude and randomly distributed when viewed versus time and concentration.Table IV

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