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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

Box plot summaries of prediction errors on EC50 for three of the eight sampling schedule scenarios: 3. (6, 8, and 24 h), 6. (1, 2, 4, 6, 8, 12, 18, and 24 h), and 8. no PK samples.
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Fig7: Box plot summaries of prediction errors on EC50 for three of the eight sampling schedule scenarios: 3. (6, 8, and 24 h), 6. (1, 2, 4, 6, 8, 12, 18, and 24 h), and 8. no PK samples.

Mentions: The resulting box-plot summaries for the PK-PD simulation prediction errors on clearance and EC50 are illustrated in Figs. 6 and 7, respectively. The first four sampling scenarios with post-PD sampling (6 h or later) demonstrated that improved predictability of clearance occurred when more post-PD samples were obtained. Notably, improvements in both bias and precision were seen as the number of samples increased. However, sampling scenario 4 with eight PK samples was only slightly better than scenario 3 with only three post-PD samples. Sampling on another occasion, even with eight samples spaced throughout the experiment at equivalent times to scenario 5, was no better than obtaining no samples at all (comparable bias and precision for scenarios 5 and 8). Scenario 6 represented the hypothetical best-case situation if dense blood samples were taken throughout the experiment. The bias was negligible and the precision was the tightest for this scenario; however, the bias was comparable and the precision only slightly better than both scenarios 3 and 4. Adding a single sample during the PD portion of the experiment (0–6 h) in scenario 7 was of no added value in comparison with scenario 2 where two samples were taken after the PD experiment. Finally, scenario 8 served as a point of comparison where no PK samples were taken. As expected, this produced the most imprecise estimates and introduced the largest amount of prediction error, along with scenario 5 where blood samples were taken in the same animal, but on a separate occasion. There was no bias in this schedule as the typical parameter values were assumed for all individuals. PD simulations reflected these conclusions for the three simulated sampling schedules.Fig. 6


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)

Box plot summaries of prediction errors on EC50 for three of the eight sampling schedule scenarios: 3. (6, 8, and 24 h), 6. (1, 2, 4, 6, 8, 12, 18, and 24 h), and 8. no PK samples.
© Copyright Policy
Related In: Results  -  Collection

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

Fig7: Box plot summaries of prediction errors on EC50 for three of the eight sampling schedule scenarios: 3. (6, 8, and 24 h), 6. (1, 2, 4, 6, 8, 12, 18, and 24 h), and 8. no PK samples.
Mentions: The resulting box-plot summaries for the PK-PD simulation prediction errors on clearance and EC50 are illustrated in Figs. 6 and 7, respectively. The first four sampling scenarios with post-PD sampling (6 h or later) demonstrated that improved predictability of clearance occurred when more post-PD samples were obtained. Notably, improvements in both bias and precision were seen as the number of samples increased. However, sampling scenario 4 with eight PK samples was only slightly better than scenario 3 with only three post-PD samples. Sampling on another occasion, even with eight samples spaced throughout the experiment at equivalent times to scenario 5, was no better than obtaining no samples at all (comparable bias and precision for scenarios 5 and 8). Scenario 6 represented the hypothetical best-case situation if dense blood samples were taken throughout the experiment. The bias was negligible and the precision was the tightest for this scenario; however, the bias was comparable and the precision only slightly better than both scenarios 3 and 4. Adding a single sample during the PD portion of the experiment (0–6 h) in scenario 7 was of no added value in comparison with scenario 2 where two samples were taken after the PD experiment. Finally, scenario 8 served as a point of comparison where no PK samples were taken. As expected, this produced the most imprecise estimates and introduced the largest amount of prediction error, along with scenario 5 where blood samples were taken in the same animal, but on a separate occasion. There was no bias in this schedule as the typical parameter values were assumed for all individuals. PD simulations reflected these conclusions for the three simulated sampling schedules.Fig. 6

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