Summary: STATISTICS IN MEDICINE
Statist. Med. 2003; 22:833ş846 (DOI: 10.1002/sim.1448)
Population pharmacokinetics=pharmacodynamics relationships
of an anticancer drug
C├ecile An├e and Didier Concordet;
UMR 181; Physiopathologie et Toxicologie Exp├erimentales; Ecole V├et├erinaire de Toulouse; 23 chemin des
Capelles; 31076 Toulouse Cedex; France
This paper proposes a method for studying the toxicity of an anticancer drug with a delayed e ect.
The goal is to predict a dosage regimen with controlled toxicity. To this end, a semi-physiological
model is used. A limit of toxicity is demonstrated, which is intrinsic to the model. It reduces the e ect
of high drug concentrations. This limit explains the mixed behaviour of the drug: time-dependence
and concentration-dependence, according to the dose actually administered. A population analysis is
performed to estimate the parameters of the model, and to predict a safe dosage regimen. Copyright ?
2003 John Wiley & Sons, Ltd.
KEY WORDS: pharmacokinetics; pharmacodynamics; non-linear mixed e ects models; toxicity
A primary goal when using an anticancer drug is to control its toxicity on patients. Since these
drugs usually have a narrow therapeutic index, the dose has to be adjusted carefully to nd an
admissible regimen which is e ective and yet not too toxic. Topotecan is an anticancer drug