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

Danhof M - J Pharmacokinet Pharmacodyn (2015)

Bottom Line: 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.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.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).

View Article: PubMed Central - PubMed

Affiliation: Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands. m.danhof@lacdr.leidenuniv.nl.

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.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of physiology-based pharmacodynamic (PBPD) modeling. PBPD models connect pharmacokinetics to the drug effects on disease progression, and contain expressions to describe the processes on the causal path between drug administration and effect (target site distribution, target binding and activation, and transduction and homeostatic feedback)
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Fig2: Schematic representation of physiology-based pharmacodynamic (PBPD) modeling. PBPD models connect pharmacokinetics to the drug effects on disease progression, and contain expressions to describe the processes on the causal path between drug administration and effect (target site distribution, target binding and activation, and transduction and homeostatic feedback)

Mentions: 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. PBPD models connect pharmacokinetics to ultimately the drug effects on disease progression (Fig. 2). As is the case for PBPK models, an important feature of PBPD models is the strict separation between drug specific properties (in terms of the binding and activation of the target) and system-specific properties (in terms of transduction processes).Fig. 2


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

Danhof M - J Pharmacokinet Pharmacodyn (2015)

Schematic representation of physiology-based pharmacodynamic (PBPD) modeling. PBPD models connect pharmacokinetics to the drug effects on disease progression, and contain expressions to describe the processes on the causal path between drug administration and effect (target site distribution, target binding and activation, and transduction and homeostatic feedback)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4582079&req=5

Fig2: Schematic representation of physiology-based pharmacodynamic (PBPD) modeling. PBPD models connect pharmacokinetics to the drug effects on disease progression, and contain expressions to describe the processes on the causal path between drug administration and effect (target site distribution, target binding and activation, and transduction and homeostatic feedback)
Mentions: 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. PBPD models connect pharmacokinetics to ultimately the drug effects on disease progression (Fig. 2). As is the case for PBPK models, an important feature of PBPD models is the strict separation between drug specific properties (in terms of the binding and activation of the target) and system-specific properties (in terms of transduction processes).Fig. 2

Bottom Line: 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.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.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).

View Article: PubMed Central - PubMed

Affiliation: Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands. m.danhof@lacdr.leidenuniv.nl.

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.

No MeSH data available.


Related in: MedlinePlus