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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

PK–PD modeling of anti-lipolytic effects of Adenosine A1 receptor agonists in rats: prediction of tissue-dependent efficacy in vivo. a Relationship between intrinsic efficacy in an in vitro (GTP-shift) and in vivo (log τ) bioassay for the effect of a series of A1 receptor agonists on heart rate and lipolysis (as measured by nonesterified fatty acids, NEFAs), respectively. The difference in the intercept for the two effects is explained by the difference in receptor density between adipose tissue and cardiac tissue. b Relationship between intrinsic efficacy in an in vitro bioassay (GTP shift) and in vivo intrinsic activity (α) for the effects on heart rate and lipolysis, respectively. The graphs show that partial agonists with GTP shift values between 1 and 5 display the highest selectivity of action for the effect lipolysis versus heart rate. Reproduced from van der Graaf et al. [70]
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Fig4: PK–PD modeling of anti-lipolytic effects of Adenosine A1 receptor agonists in rats: prediction of tissue-dependent efficacy in vivo. a Relationship between intrinsic efficacy in an in vitro (GTP-shift) and in vivo (log τ) bioassay for the effect of a series of A1 receptor agonists on heart rate and lipolysis (as measured by nonesterified fatty acids, NEFAs), respectively. The difference in the intercept for the two effects is explained by the difference in receptor density between adipose tissue and cardiac tissue. b Relationship between intrinsic efficacy in an in vitro bioassay (GTP shift) and in vivo intrinsic activity (α) for the effects on heart rate and lipolysis, respectively. The graphs show that partial agonists with GTP shift values between 1 and 5 display the highest selectivity of action for the effect lipolysis versus heart rate. Reproduced from van der Graaf et al. [70]

Mentions: A milestone in the research on pharmacodynamics was the incorporation of concepts from receptor theory for the prediction of variation in concentration–effect relations [65]. In theory, the relationship between the drug concentration and the intensity of the biological response depends on drug- and biological system specific factors (Fig. 3). This explains why for a given drug, the concentration–effect relationship can differ between tissues, between species and, within a single species, also between individuals. Classical receptor theory combines two independent parts to describe drug action: an agonist-dependent part and a system dependent part and therefore constitute a unique scientific basis for the prediction of variation in in vivo concentration–effect relationships Briefly, the agonist dependent part describes the target activation, usually on the basis of a hyperbolic function. The target activation depends on the intrinsic efficacy of the drug under investigation and the receptor density. Next the system dependent part describes the translation of the target activation into the response on the basis of a system-specific transducer function. This transducer function can take any shape (i.e. linear, hyperbolic) [65]. In a number of investigations it was shown that for a given target, receptor models can be identified by simultaneously analyzing concentration–effect relations of a training set of ligands with different binding affinity and intrinsic efficacy, yielding estimates of the in vivo binding affinity and intrinsic efficacy of each of the drugs in the training set, as well as the shape and location of the system specific non-linear transducer function. For GABAA-receptor agonists, adenosine A1 receptor agonists, (semi-) synthetic opioids and 5-HT1A receptor agonists highly significant correlations were observed between the affinity and intrinsic efficacy estimates in vivo and corresponding estimates in in vitro bioassays confirming the validity of the approach [64, 66–68]. Thereby it was demonstrated that for individual compounds, in vivo drug concentration–effect relationships can be predicted on the basis of information from these in vitro assays, provided that the effects of potentially confounding pharmacokinetic factors are either excluded or accounted for, as was demonstrated for the 5-HT1A receptor agonist flesinoxan, which has a much lower in vivo potency than expected on the basis of its receptor affinity, due to active efflux mechanisms at the blood–brain barrier [69]. Successful applications of receptor theory include prediction of the selectivity of action of N6 cyclopentyladenosine analogues (inhibition of lipolysis versus bradycardia [70]; Fig. 4), prediction of the selectivity of action of semi-synthetic opioids (anti-nociception versus respiratory depression [71]), prediction of concentration–effect relations of (semi-) synthetic opioids in man [72, 73], and the prediction of variation in concentration–effect relations of alfentanil (Fig. 5) [74].Fig. 3


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

Danhof M - J Pharmacokinet Pharmacodyn (2015)

PK–PD modeling of anti-lipolytic effects of Adenosine A1 receptor agonists in rats: prediction of tissue-dependent efficacy in vivo. a Relationship between intrinsic efficacy in an in vitro (GTP-shift) and in vivo (log τ) bioassay for the effect of a series of A1 receptor agonists on heart rate and lipolysis (as measured by nonesterified fatty acids, NEFAs), respectively. The difference in the intercept for the two effects is explained by the difference in receptor density between adipose tissue and cardiac tissue. b Relationship between intrinsic efficacy in an in vitro bioassay (GTP shift) and in vivo intrinsic activity (α) for the effects on heart rate and lipolysis, respectively. The graphs show that partial agonists with GTP shift values between 1 and 5 display the highest selectivity of action for the effect lipolysis versus heart rate. Reproduced from van der Graaf et al. [70]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: PK–PD modeling of anti-lipolytic effects of Adenosine A1 receptor agonists in rats: prediction of tissue-dependent efficacy in vivo. a Relationship between intrinsic efficacy in an in vitro (GTP-shift) and in vivo (log τ) bioassay for the effect of a series of A1 receptor agonists on heart rate and lipolysis (as measured by nonesterified fatty acids, NEFAs), respectively. The difference in the intercept for the two effects is explained by the difference in receptor density between adipose tissue and cardiac tissue. b Relationship between intrinsic efficacy in an in vitro bioassay (GTP shift) and in vivo intrinsic activity (α) for the effects on heart rate and lipolysis, respectively. The graphs show that partial agonists with GTP shift values between 1 and 5 display the highest selectivity of action for the effect lipolysis versus heart rate. Reproduced from van der Graaf et al. [70]
Mentions: A milestone in the research on pharmacodynamics was the incorporation of concepts from receptor theory for the prediction of variation in concentration–effect relations [65]. In theory, the relationship between the drug concentration and the intensity of the biological response depends on drug- and biological system specific factors (Fig. 3). This explains why for a given drug, the concentration–effect relationship can differ between tissues, between species and, within a single species, also between individuals. Classical receptor theory combines two independent parts to describe drug action: an agonist-dependent part and a system dependent part and therefore constitute a unique scientific basis for the prediction of variation in in vivo concentration–effect relationships Briefly, the agonist dependent part describes the target activation, usually on the basis of a hyperbolic function. The target activation depends on the intrinsic efficacy of the drug under investigation and the receptor density. Next the system dependent part describes the translation of the target activation into the response on the basis of a system-specific transducer function. This transducer function can take any shape (i.e. linear, hyperbolic) [65]. In a number of investigations it was shown that for a given target, receptor models can be identified by simultaneously analyzing concentration–effect relations of a training set of ligands with different binding affinity and intrinsic efficacy, yielding estimates of the in vivo binding affinity and intrinsic efficacy of each of the drugs in the training set, as well as the shape and location of the system specific non-linear transducer function. For GABAA-receptor agonists, adenosine A1 receptor agonists, (semi-) synthetic opioids and 5-HT1A receptor agonists highly significant correlations were observed between the affinity and intrinsic efficacy estimates in vivo and corresponding estimates in in vitro bioassays confirming the validity of the approach [64, 66–68]. Thereby it was demonstrated that for individual compounds, in vivo drug concentration–effect relationships can be predicted on the basis of information from these in vitro assays, provided that the effects of potentially confounding pharmacokinetic factors are either excluded or accounted for, as was demonstrated for the 5-HT1A receptor agonist flesinoxan, which has a much lower in vivo potency than expected on the basis of its receptor affinity, due to active efflux mechanisms at the blood–brain barrier [69]. Successful applications of receptor theory include prediction of the selectivity of action of N6 cyclopentyladenosine analogues (inhibition of lipolysis versus bradycardia [70]; Fig. 4), prediction of the selectivity of action of semi-synthetic opioids (anti-nociception versus respiratory depression [71]), prediction of concentration–effect relations of (semi-) synthetic opioids in man [72, 73], and the prediction of variation in concentration–effect relations of alfentanil (Fig. 5) [74].Fig. 3

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