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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

a Schematic representation of drug concentration versus time profiles at three different infusion rates in the plasma (continuous lines) and at the site of action (dashed lines). The time of onset of a pharmacologic effect is indicated by arrows. The representation is a simulation of a two-compartment system with a drug clearance of 0.029 l/h, a terminal drug half-life of 24 h and infusion rates of 0.42, 2.5 and 4.2 mg/min. It should be noted that the drug concentration in plasma at onset of effect decreases with decreasing infusion rate. b Effect of infusion rate on the concentration of phenobarbital in serum (total and unbound drug, respectively), brain and CSF of female rats at the onset of loss of righting reflex. Results are the mean of five to nine animals per group, with the vertical line indicating 1 SD. Infusion rate had a significant effect (p < 0.001 by one-way analysis of variance) on drug concentrations in serum and brain but not on concentrations in CSF. The symbols above the vertical bars indicate significant differences from the results produced by the lowest infusion rate (*p < 0.002; ‡p < 0.01; +p < 0.05; Newman-Keuls test). Reproduced from Danhof and Levy 1984 [5]
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Fig1: a Schematic representation of drug concentration versus time profiles at three different infusion rates in the plasma (continuous lines) and at the site of action (dashed lines). The time of onset of a pharmacologic effect is indicated by arrows. The representation is a simulation of a two-compartment system with a drug clearance of 0.029 l/h, a terminal drug half-life of 24 h and infusion rates of 0.42, 2.5 and 4.2 mg/min. It should be noted that the drug concentration in plasma at onset of effect decreases with decreasing infusion rate. b Effect of infusion rate on the concentration of phenobarbital in serum (total and unbound drug, respectively), brain and CSF of female rats at the onset of loss of righting reflex. Results are the mean of five to nine animals per group, with the vertical line indicating 1 SD. Infusion rate had a significant effect (p < 0.001 by one-way analysis of variance) on drug concentrations in serum and brain but not on concentrations in CSF. The symbols above the vertical bars indicate significant differences from the results produced by the lowest infusion rate (*p < 0.002; ‡p < 0.01; +p < 0.05; Newman-Keuls test). Reproduced from Danhof and Levy 1984 [5]

Mentions: 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 (loss of righting reflex, LRR) to identify a site where drug concentrations were in direct equilibrium with the target site, to ultimately be able to study changes in the brain sensitivity to sedative and anesthetic drugs [5]. For this first study, phenobarbital was chosen as a model drug, because of its favorable pharmacokinetic properties, in that unlike many other barbiturates, phenobarbital is not an enantiomeric drug. Moreover, the drug is slowly metabolized and p-hydroxy-phenobarbital had been identified as its major metabolite, which was commercially available, and of which the effects could be studied. A specific feature of using drug concentrations at the onset of LRR as pharmacodynamic endpoint (rather than the more traditional approach of measuring the concentration at offset in a sleeping time experiment) is that the concentrations are obtained under disequilibrium conditions. This enables identification of the compartment which is indistinguishable from the site of action, which is the compartment where the free drug concentration at onset of LRR is independent of the rate of infusion (Fig. 1a). These studies showed that only in cerebrospinal fluid (CSF), but not in plasma or brain tissue, the phenobarbital concentration at onset of LRR is independent of the infusion rate. Thus, in this manner the CSF was identified as a compartment that, unlike blood plasma or whole brain tissue, is pharmacokinetically indistinguishable from the site of action (Fig. 1b) [5]. A further advantage of the use of CSF concentrations is that, due to the absence of significant protein concentrations, they reflect free drug concentrations in the brain which presumably are pharmacologically more relevant compared to total brain concentrations. In subsequent investigations from Levy’s laboratory and others these investigations were extended to different drugs and different pharmacodynamic endpoints (Table 1). For example studies on the sedative effects were extended to other barbiturates with different physicochemical properties(e.g. heptabarbital) and drugs with different molecular targets such as, ethanol [10] benzodiazepines (e.g. diazepam, oxazepam [11, 12]), zoxazolamine (and its metabolite chlorzoxazone, [13]), and salicylamide [14]. Next the studies were extended to other pharmacodynamic endpoints (e.g. convulsant effects of pentylenetetrazole, PTZ) [15, 16]. These studies showed that for most of the drugs studied, the CSF concentrations are uniquely representative for the target site concentrations, while for other drugs (salicylamide and PTZ) there is rapid equilibrium between the concentrations in plasma, brain tissue, and CSF making them equally useful for use in pharmacodynamic investigations (Table 1). The principles of identifying a compartment in which drug concentrations are in direct equilibrium with effect site concentrations, and the use of CSF in pharmacodynamic studies on CNS active drugs were adopted by other research groups [17–21]. This generated an interest in the use of CSF drug concentrations in investigations on the pharmacodynamics of CNS active drugs (for review see: [22]).Fig. 1


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

Danhof M - J Pharmacokinet Pharmacodyn (2015)

a Schematic representation of drug concentration versus time profiles at three different infusion rates in the plasma (continuous lines) and at the site of action (dashed lines). The time of onset of a pharmacologic effect is indicated by arrows. The representation is a simulation of a two-compartment system with a drug clearance of 0.029 l/h, a terminal drug half-life of 24 h and infusion rates of 0.42, 2.5 and 4.2 mg/min. It should be noted that the drug concentration in plasma at onset of effect decreases with decreasing infusion rate. b Effect of infusion rate on the concentration of phenobarbital in serum (total and unbound drug, respectively), brain and CSF of female rats at the onset of loss of righting reflex. Results are the mean of five to nine animals per group, with the vertical line indicating 1 SD. Infusion rate had a significant effect (p < 0.001 by one-way analysis of variance) on drug concentrations in serum and brain but not on concentrations in CSF. The symbols above the vertical bars indicate significant differences from the results produced by the lowest infusion rate (*p < 0.002; ‡p < 0.01; +p < 0.05; Newman-Keuls test). Reproduced from Danhof and Levy 1984 [5]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig1: a Schematic representation of drug concentration versus time profiles at three different infusion rates in the plasma (continuous lines) and at the site of action (dashed lines). The time of onset of a pharmacologic effect is indicated by arrows. The representation is a simulation of a two-compartment system with a drug clearance of 0.029 l/h, a terminal drug half-life of 24 h and infusion rates of 0.42, 2.5 and 4.2 mg/min. It should be noted that the drug concentration in plasma at onset of effect decreases with decreasing infusion rate. b Effect of infusion rate on the concentration of phenobarbital in serum (total and unbound drug, respectively), brain and CSF of female rats at the onset of loss of righting reflex. Results are the mean of five to nine animals per group, with the vertical line indicating 1 SD. Infusion rate had a significant effect (p < 0.001 by one-way analysis of variance) on drug concentrations in serum and brain but not on concentrations in CSF. The symbols above the vertical bars indicate significant differences from the results produced by the lowest infusion rate (*p < 0.002; ‡p < 0.01; +p < 0.05; Newman-Keuls test). Reproduced from Danhof and Levy 1984 [5]
Mentions: 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 (loss of righting reflex, LRR) to identify a site where drug concentrations were in direct equilibrium with the target site, to ultimately be able to study changes in the brain sensitivity to sedative and anesthetic drugs [5]. For this first study, phenobarbital was chosen as a model drug, because of its favorable pharmacokinetic properties, in that unlike many other barbiturates, phenobarbital is not an enantiomeric drug. Moreover, the drug is slowly metabolized and p-hydroxy-phenobarbital had been identified as its major metabolite, which was commercially available, and of which the effects could be studied. A specific feature of using drug concentrations at the onset of LRR as pharmacodynamic endpoint (rather than the more traditional approach of measuring the concentration at offset in a sleeping time experiment) is that the concentrations are obtained under disequilibrium conditions. This enables identification of the compartment which is indistinguishable from the site of action, which is the compartment where the free drug concentration at onset of LRR is independent of the rate of infusion (Fig. 1a). These studies showed that only in cerebrospinal fluid (CSF), but not in plasma or brain tissue, the phenobarbital concentration at onset of LRR is independent of the infusion rate. Thus, in this manner the CSF was identified as a compartment that, unlike blood plasma or whole brain tissue, is pharmacokinetically indistinguishable from the site of action (Fig. 1b) [5]. A further advantage of the use of CSF concentrations is that, due to the absence of significant protein concentrations, they reflect free drug concentrations in the brain which presumably are pharmacologically more relevant compared to total brain concentrations. In subsequent investigations from Levy’s laboratory and others these investigations were extended to different drugs and different pharmacodynamic endpoints (Table 1). For example studies on the sedative effects were extended to other barbiturates with different physicochemical properties(e.g. heptabarbital) and drugs with different molecular targets such as, ethanol [10] benzodiazepines (e.g. diazepam, oxazepam [11, 12]), zoxazolamine (and its metabolite chlorzoxazone, [13]), and salicylamide [14]. Next the studies were extended to other pharmacodynamic endpoints (e.g. convulsant effects of pentylenetetrazole, PTZ) [15, 16]. These studies showed that for most of the drugs studied, the CSF concentrations are uniquely representative for the target site concentrations, while for other drugs (salicylamide and PTZ) there is rapid equilibrium between the concentrations in plasma, brain tissue, and CSF making them equally useful for use in pharmacodynamic investigations (Table 1). The principles of identifying a compartment in which drug concentrations are in direct equilibrium with effect site concentrations, and the use of CSF in pharmacodynamic studies on CNS active drugs were adopted by other research groups [17–21]. This generated an interest in the use of CSF drug concentrations in investigations on the pharmacodynamics of CNS active drugs (for review see: [22]).Fig. 1

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