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A Population Pharmacokinetic Model with Time-Dependent Covariates Measured with Errors

Lang Li, Xihong Lin, Morton B. Brown, Suneel Gupta and Kyung-Hoon Lee
Biometrics
Vol. 60, No. 2 (Jun., 2004), pp. 451-460
Stable URL: http://www.jstor.org/stable/3695773
Page Count: 10
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A Population Pharmacokinetic Model with Time-Dependent Covariates Measured with Errors
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Abstract

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.

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