Kinetics of drug action in disease states: towards physiology-based pharmacodynamic (PBPD) models.

Meindert Danhof

doi:10.1007/s10928-015-9437-x

Abstract

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.

Highlights

Gerhard Levy started his investigations in the series ‘‘Kinetics of Drug Action in Disease States’’, in the fall of 1980
At that time it was well-established that multiple factors including certain diseases, changes in physiology, concomitant use of other drugs and environmental factors can have profound effects on the pharmacokinetics of drugs [1]
In the first paper in the series on the kinetics of drug action in disease states, we introduced the concept of infusion of sedative drugs to a predefined degree of sedation to identify a site where drug concentrations were in direct equilibrium with the target site, to be able to study changes in the brain sensitivity to sedative and anesthetic drugs [5]

Summary

Introduction

Gerhard Levy started his investigations in the series ‘‘Kinetics of Drug Action in Disease States’’, in the fall of 1980. To this end the influence of the infusion rate on the phenobarbital plasma, tissue and CSF concentrations at onset of LRR was determined in rats with experimental renal failure.

Results

Conclusion