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Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling—A New Classification of Biomarkers

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Abstract

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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Authors and Affiliations

  1. Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands

    Meindert Danhof

  2. Medical Products Agency, 75125, Uppsala, Sweden

    Gunnar Alvan

  3. Department of Pharmacology, Faculty of Medicine, University of Tromsø, 9037, Tromsø, Norway

    Svein G. Dahl

  4. Institute of Clinical Pharmacology, Bayer HealthCare AG, Business Group Pharma, Pharma-Research-Center, 42096, Wuppertal, Germany

    Jochen Kuhlmann

  5. Laboratory of Pharmacology, Faculty of Medicine, François-Rabelais University, 37032, Tours, France

    Gilles Paintaud

Authors
  1. Meindert Danhof
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  2. Gunnar Alvan
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  3. Svein G. Dahl
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  4. Jochen Kuhlmann
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  5. Gilles Paintaud
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Correspondence to Meindert Danhof.

Additional information

This paper is based in part on discussions at a COST B15 expert meeting in Leiden, the Netherlands, on April 27–28, 2000. Participating experts were Gunnar Alvan (Sweden), Svein G. Dahl (Norway), Jochen Kuhlmann (Germany), Gilles Paintaud (France), Lars Farde (Sweden), Mats Karlsson (Sweden), Stephen Fey (Denmark), Munir Pirmohamed (UK), Paul Rolan (UK), Matthias Büchler (France), Joop van Gerven (Netherlands), Piet Van der Graaf (UK), Kees Kluft (Netherlands), Nick H.G. Holford (New Zealand), Oscar E. Della Pasqua (Netherlands/UK), Olavi Pelkonen (Finland).

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Danhof, M., Alvan, G., Dahl, S.G. et al. Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling—A New Classification of Biomarkers. Pharm Res 22, 1432–1437 (2005). https://doi.org/10.1007/s11095-005-5882-3

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