Relationships Between Intra- Or Interindividual Variability and Biological Covariates: Application to Zidovudine Pharmacokinetics
Quantification of interindividual variability and determination of the covariates contributing to this variability have proved to improve decision-making procedures and individualization of dosage regimen. Several methods have been developed to estimate the probability distribution of the pharmacokinetic parameters from measurements obtained in a sample of individuals. All these methods assume that parameters and covariates remain stationary within an individual. However, ascertaining the stationarity of the parameters or quantifying intraindividual variability can be important when chronic administration is scheduled. We propose a population approach to study the stationarity of the pharmacokinetic parameters. This method is developed around the Non-Parametric Maximum Likelihood estimation method and is based on the comparison of the likelihood of two samples of data from the same individuals at two different times under several assumptions. Some ideas to study stationarity of both individual pharmacokinetic parameters and covariates are also given. The proposed method is illustrated on a very simple simulated example which reflects continuous infusion of a drug involving various assumptions about the nonstationarity of the parameters. The approach is then applied to population analysis of zidovudine kinetics data measured on the first and 35th day of therapy in 36 patients.
KeywordsPharmacokinetic Parameter Conditional Distribution Interindividual Variability Population Pharmacokinetic Intraindividual Variability
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