caa a22 4500 605534098 CHVBK 20210128100841.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s10928-015-9437-x doi (NATIONALLICENCE)springer-10.1007/s10928-015-9437-x Danhof Meindert Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands aut Kinetics of drug action in disease states: towards physiology-based pharmacodynamic (PBPD) models [Elektronische Daten] [Meindert Danhof] Gerhard Levy started his investigations on the "Kinetics of Drug Action in Disease States” in the fall of 1980. The objective of his research was to study inter-individual variation in pharmacodynamics. To this end, theoretical concepts and experimental approaches were introduced, which enabled assessment of the changes in pharmacodynamics per se, while excluding or accounting for the cofounding effects of concomitant changes in pharmacokinetics. These concepts were applied in several studies. The results, which were published in 45 papers in the years 1984-1994, showed considerable variation in pharmacodynamics. These initial studies on kinetics of drug action in disease states triggered further experimental research on the relations between pharmacokinetics and pharmacodynamics. Together with the concepts in Levy's earlier publications "Kinetics of Pharmacologic Effects” (Clin Pharmacol Ther 7(3): 362-372, 1966) and "Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin” (Clin Pharmacol Ther 10(1): 22-35, 1969), they form a significant impulse to the development of physiology-based pharmacodynamic (PBPD) modeling as novel discipline in the pharmaceutical sciences. This paper reviews Levy's research on the "Kinetics of Drug Action in Disease States”. Next it addresses the significance of his research for the evolution of PBPD modeling as a scientific discipline. PBPD models contain specific expressions to characterize in a strictly quantitative manner processes on the causal path between exposure (in terms of concentration at the target site) and the drug effect (in terms of the change in biological function). Pertinent processes on the causal path are: (1) target site distribution, (2) target binding and activation and (3) transduction and homeostatic feedback. The Author(s), 2015 Biophase distribution nationallicence Receptor theory nationallicence Dynamical systems analysis nationallicence Disease systems analysis nationallicence Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/5(2015-10-01), 447-462 1567-567X 42:5<447 2015 42 10928 https://doi.org/10.1007/s10928-015-9437-x text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 review-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9437-x text/html Onlinezugriff via DOI NATIONALLICENCE 100 1- Danhof Meindert Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/5(2015-10-01), 447-462 1567-567X 42:5<447 2015 42 10928