Lang Li

School of Medicine, Medical & Molecular Genetics

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A population pharmacokinetic model with time-dependent covariates measured with errors

Lang Li; Xihong Lin; Morton B. Brown; Suneel Gupta; Kyung-Hoon Lee (Profiled Author: Lang Li)

Biometrics. 2004;60(2):451-460.

We propose a population pharmacokinetic (PK) model with time-dependent covariates measured with errors. This model is used to model S-oxybutynin's kinetics following an oral administration of Ditropan, and allows the distribution rate to depend on time-dependent covariates blood pressure and heart rate, which are measured with errors. We propose two two-step estimation methods: the second-order two-step method with numerical solutions of differential equations (2orderND), and the second-order two-step method with closed form approximate solutions of differential equations (2orderAD). The proposed methods are computationally easy and require fitting a linear mixed model at the first step and a nonlinear mixed model at the second step. We apply the proposed methods to the analysis of the Ditropan data, and evaluate their performance using a simulation study. Our results show that the 2orderND method performs well, while the 2orderAD method can yield PK parameter estimators that are subject to considerable biases.

PMID: 15180671    

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