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A Population Pharmacokinetic Model with Time‐Dependent Covariates Measured with Errors
Author(s) -
Li Lang,
Lin Xihong,
Brown Morton B.,
Gupta Suneel,
Lee KyungHoon
Publication year - 2004
Publication title -
biometrics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.298
H-Index - 130
eISSN - 1541-0420
pISSN - 0006-341X
DOI - 10.1111/j.0006-341x.2004.00190.x
Subject(s) - covariate , statistics , econometrics , population , pharmacokinetics , mathematics , computer science , medicine , environmental health
Summary . 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.