title: An interface model for dosage adjustment connects hematotoxicity to pharmacokinetics.
abstract: When modeling is required to describe pharmacokinetics and pharmacodynamics simultaneously, it is difficult to link time-concentration profiles and drug effects. When patients are under chemotherapy, despite the huge amount of blood monitoring numerations, there is a lack of exposure variables to describe hematotoxicity linked with the circulating drug blood levels. We developed an interface model that transforms circulating pharmacokinetic concentrations to adequate exposures, destined to be inputs of the pharmacodynamic process. The model is materialized by a nonlinear differential equation involving three parameters. The relevance of the interface model for dosage adjustment is illustrated by numerous simulations. In particular, the interface model is incorporated into a complex system including pharmacokinetics and neutropenia induced by docetaxel and by cisplatin. Emphasis is placed on the sensitivity of neutropenia with respect to the variations of the drug amount. This complex system including pharmacokinetic, interface, and pharmacodynamic hematotoxicity models is an interesting tool for analysis of hematotoxicity induced by anticancer agents. The model could be a new basis for further improvements aimed at incorporating new experimental features.
authors.affiliation: Department of Pharmacokinetics, Faculty of Pharmacy, University of Méditerranée, EA3286, 27, bd. Jean Moulin, 13385, Marseilles Cedex 5, France.
authors.forename: C
authors.initials: C
authors.lastname: Meille
authors.forename: A
authors.initials: A
authors.lastname: Iliadis
authors.forename: D
authors.initials: D
authors.lastname: Barbolosi
authors.forename: N
authors.initials: N
authors.lastname: Frances
authors.forename: G
authors.initials: G
authors.lastname: Freyer
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003198:Computer Simulation; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D006801:Humans; D008954:Models, Biological; D009503:Neutropenia / Q000139:chemically induced*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin