Cisplatin pharmacokinetics: applications of a physiological model

A physiological pharmacokinetic model for the disposition of the antineoplastic drug cis-diamminedichloroplatinum(II) (cisplatin or DDP) in several mammalian species is reviewed. The significance of the model's key parameters and of their interspecies relationships is discussed. Methods for estimating two of these parameters (the rate constants for formation of the fixed and mobile metabolites) from in vitro experiments are presented. Fixed and mobile metabolites are formed by the irreversible binding of cisplatin to macromolecules and low molecular weight nucleophiles, respectively. Use of the model to simulate and predict the pharmacokinetic behavior of cisplatin and its metabolites in different animal species following intravenous and intraperitoneal administration is illustrated. Fixed metabolite formation rate constants can be used in conjunction with mass transport parameters to estimate tissue exposures to cisplatin following systemic or regional drug administration. The model logically can serve as the basis for a pharmacodynamic model that incorporates cisplatin reactions with DNA. The model also provides a means for comparing the pharmacokinetic characteristics of cisplatin analogs and for assisting in rational analog development.