Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
Pharm Res. 2009 Oct;26(10):2259-69. doi: 10.1007/s11095-009-9942-y. Epub 2009 Aug 11.
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.
初步证据表明，普瑞巴林与西地那非联合治疗神经病理性疼痛具有协同作用。本研究的重点是确定西地那非对普瑞巴林药代动力学（PK）的影响，旨在为定量药效学（PD）研究的设计提供信息。
在给予大鼠 4 mg/kg/hr 和 10 mg/kg/hr 的普瑞巴林静脉输注 2 小时后，给予或不给予西地那非推注（2.2 mg）和稳态输注（6 小时内 12 mg/kg/hr），以确定西地那非对 pregabalin 的药代动力学（PK）的影响。利用该 PK 模型进行临床前试验模拟，旨在选择最佳采样策略，以在未来的研究中描述 PK-PD 特征。通过试验模拟技术，在 NONMEM 中模拟了 8 种逻辑可行的 PK 采样策略，并进行了检验。
两室人群 PK 模型最能描述普瑞巴林的药代动力学。显著的模型协变量包括西地那非给药的二进制效应（清除率降低 30.2%）或西地那非活性代谢物的浓度依赖性效应。
模拟分析表明，与不进行 PK 采样相比，三个 PD 后采样具有最佳的成本效益比，因为与 PK 采样相比，它可以显著提高 PK 和 PD 参数的精度（并略有改善偏差）。
