Mechanism-based pharmacokinetic-pharmacodynamic modeling-a new classification of biomarkers

In recent years, pharmacokinetic/pharmacodynamic (PK/PD) modeling has developed from an empirical descriptive discipline into a mechanistic science that can be applied at all stages of drug development. Mechanism-based PK/PD models differ from empirical descriptive models in that they contain specif...

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Published inPharmaceutical research Vol. 22; no. 9; pp. 1432 - 1437
Main Authors Danhof, Meindert, Alvan, Gunnar, Dahl, Svein G, Kuhlmann, Jochen, Paintaud, Gilles
Format Journal Article
LanguageEnglish
Published United States Springer Nature B.V 01.09.2005
Subjects
Biomarkers
Classification
Clinical trials
Drugs
Nervous system
Pharmacodynamics
Pharmacokinetics
Pharmacology
Physiology
R&D
Research & development
Sweden
Netherlands
United Kingdom > UK
France
Norway
Germany
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Summary:In recent years, pharmacokinetic/pharmacodynamic (PK/PD) modeling has developed from an empirical descriptive discipline into a mechanistic science that can be applied at all stages of drug development. Mechanism-based PK/PD models differ from empirical descriptive models in that they contain specific expressions to characterize processes on the causal path between drug administration and effect. Mechanism-based PK/PD models have much improved properties for extrapolation and prediction. As such, they constitute a scientific basis for rational drug discovery and development. In this report, a novel classification of biomarkers is proposed. Within the context of mechanism-based PK/PD modeling, a biomarker is defined as a measure that characterizes, in a strictly quantitative manner, a process, which is on the causal path between drug administration and effect. The new classification system distinguishes seven types of biomarkers: type 0, genotype/phenotype determining drug response; type 1, concentration of drug or drug metabolite; type 2, molecular target occupancy; type 3, molecular target activation; type 4, physiological measures; type 5, pathophysiological measures; and type 6, clinical ratings. In this paper, the use of the new biomarker classification is discussed in the context of the application of mechanism-based PK/PD analysis in drug discovery and development.
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ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-005-5882-3