Pharmaceutical Research

, Volume 22, Issue 9, pp 1432–1437 | Cite as

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

  • Meindert Danhof
  • Gunnar Alvan
  • Svein G. Dahl
  • Jochen Kuhlmann
  • Gilles Paintaud
Research Paper


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.

Key Words

genotype molecular target activation molecular target occupancy pathophysiological measures physiological measures 


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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Meindert Danhof
    • 1
  • Gunnar Alvan
    • 2
  • Svein G. Dahl
    • 3
  • Jochen Kuhlmann
    • 4
  • Gilles Paintaud
    • 5
  1. 1.Leiden/Amsterdam Center for Drug Research, Division of PharmacologyLeiden UniversityLeidenThe Netherlands
  2. 2.Medical Products AgencyUppsalaSweden
  3. 3.Department of Pharmacology, Faculty of MedicineUniversity of TromsøTromsøNorway
  4. 4.Institute of Clinical Pharmacology, Bayer HealthCare AG, Business Group PharmaPharma-Research-CenterWuppertalGermany
  5. 5.Laboratory of Pharmacology, Faculty of MedicineFrançois-Rabelais UniversityToursFrance

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