An interface model for dosage adjustment connects hematotoxicity to pharmacokinetics

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 de...

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Bibliographic Details
Published in:Journal of pharmacokinetics and pharmacodynamics 2008-12, Vol.35 (6), p.619-633
Main Authors: Meille, C., Iliadis, A., Barbolosi, D., Frances, N., Freyer, G.
Format: Article
Language:English
Subjects:
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - adverse effects
Antineoplastic Agents - pharmacokinetics
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Cisplatin - administration & dosage
Cisplatin - adverse effects
Cisplatin - pharmacokinetics
Computer Simulation
Dose-Response Relationship, Drug
Drug Dosage Calculations
Humans
Models, Biological
Neutropenia - chemically induced
Pharmacology/Toxicology
Pharmacy
Taxoids - administration & dosage
Taxoids - adverse effects
Taxoids - pharmacokinetics
Veterinary Medicine/Veterinary Science
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Summary: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.
ISSN:1567-567X
1573-8744
DOI:10.1007/s10928-008-9106-4