A Population Pharmacokinetic Model of Gabapentin Developed in Nonparametric Adaptive Grid and Nonlinear Mixed Effects Modeling
A Population Pharmacokinetic Model of Gabapentin Developed in Nonparametric Adaptive Grid and Nonlinear Mixed Effects Modeling
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DOI：
10.1097/ftd.0b013e318194767d
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发表时间：
2009-02-01
影响因子：
2.5
通讯作者：
Hoem, Nils Ove
中科院分区：
文献类型：
--
作者：
Carlsson, Kristin C.;van de Schootbrugge, Margunn;Hoem, Nils Ove
加巴喷丁用于神经性疼痛的镇痛治疗，该药物的药代动力学（PK）存在较大的个体差异。本研究的目的是开发加巴喷丁的群体 PK 模型，适用于监测神经性疼痛患者并个性化其剂量方案。从 16 名成年患者中获得了加巴喷丁在剂量间隔内的稳态血清浓度分布。使用迭代 2 阶段贝叶斯和非参数自适应网格算法 (NPAG) (USC*PACK) 以及非线性混合效应建模 (NONMEM) 来分析数据。使用肌酐清除率和体重作为协变量，在 NPAG 和 NONMEM 中开发了加巴喷丁 PK 的区室群体模型。通过使用从先前文献报道的数据导出的双曲函数，将生物利用度作为剂量的函数包含在模型中。最终 NPAG 模型的平均群体参数估计值相当好地预测了个体血清浓度。 NONMEM 中开发的模型提供了有关各种可能协变量的相关性的附加信息，并且还允许通过模型模拟进行进一步评估。群体 PK 模型可用于 MM-USCPACK 监测软件（MM：多模型剂量设计）中，用于预测和实现单独优化的加巴喷丁稳态血清浓度。
Gabapentin is used in analgesic treatment of neuropathic pain, and large interindividual variation has been observed in the pharmacokinetics (PK) of the drug. The aim of this study was to develop a population PK model for gabapentin appropriate for monitoring patients with neuropathic pain and for individualizing their dose regimens. Steady-state serum concentrations of gabapentin, distributed over a dosage interval, were obtained from 16 adult patients. Data were analyzed with an iterative 2-stage Bayesian and a nonparametric adaptive grid algorithm (NPAG) (USC*PACK) an with nonlinear mixed effects modeling (NONMEM). Compartmental population models for gabapentin PK were developed in NPAG and NONMEM using creatinine clearance and body weight as covariates. Bioavailability was included in the models as a function of dose by using a hyperbolic function derived from data previously reported in the literature. The mean population parameter estimates from the final NPAG model predicted individual serum concentrations reasonably well. The models developed in NONMEM provided additional information about the relevance of the various possible covariates and also allowed for further evaluation by simulation from the model. The population PK model may be utilized in the MM-USCPACK monitoring software (MM: multiple model dosage design) for predicting and achieving individually optimized steady-state serum concentrations of gabapentin.