Pharmacokinetic-pharmacodynamic modelling in pre-clinical investigations: principles and perspectives.
A new approach to preclinical pharmacodynamic investigations is presented which allows, in addition to information on the nature of the pharmacological properties of new chemical entities, also important quantitative pharmacodynamic information to be derived. A single intravenous dose is administered to chronically instrumented rats and the time course of the pharmacological effect is determined in conjunction with plasma or serum concentrations. Datasets obtained in this way are subjected to simultaneous pharmacokinetic/pharmacodynamic modelling to obtain estimates of pharmacodynamic parameters such as EC50, Emax, Hill factor and the rate of biophase equilibration. The new approach was applied in studies with benzodiazepines, baclofen, antiepileptic drugs and adenosine receptor agonists and antagonists. In these studies quantitative EEG parameters, the threshold for convulsion as determined by direct cortical stimulation and various haemodynamic variables were used as a pharmacodynamic endpoint. For drugs exhibiting agonistic or inverse agonistic properties, realistic estimates of the potency and intrinsic efficacy could be obtained by modelling of the direct effects in the various effect models. Estimates of the potency of competitive antagonists (e.g. flumazenil, cyclopentyl-theophylline) could be obtained on the basis of modelling of the pharmacodynamic interaction with a full agonist. For baclofen finally also the rate of biophase equilibration could be estimated. The results of these studies show that by implementation of pharmacokinetic-pharmacodynamic modelling in pre-clinical investigations, useful quantitative information on the pharmacodynamics of new drugs in vivo can be obtained. It is suggested that this information may be of value in the early phases of pre-clinical drug development and that it may facilitate the subsequent clinical development process.
Danhof
M
M
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, University of Leiden, The Netherlands.
Mandema
J W
JW
Hoogerkamp
A
A
Mathôt
R A
RA
D000818:Animals; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics; D010600:Pharmacology; D051381:Rats