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 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.
Danhof
Meindert
M
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands. m.danhof@lacdr.leidenuniv.nl
Alvan
Gunnar
G
Dahl
Svein G
SG
Kuhlmann
Jochen
J
Paintaud
Gilles
G
D015415:Biomarkers; D010599:Pharmacokinetics; D010600:Pharmacology
D015415:Biomarkers