Extrapolation from preclinical PKPD data to clinical response, Application to a new antiepileptic medication (drug X)
Marchand, M. (1), O. Petricoul (1), E. Fuseau (1), D. Bentley (2), D. Critchley (2)
(1) EMF consulting, France. (2) EISAI Global Clinical Development, UK
Objectives: To predict clinically relevant doses of a new antiepileptic drug from preclinical data based on PKPD modelling.
Material and methods: Preclinical studies in mice: PK, maximal electroshock seizures (MES) test and pentylenetetrazole-induced seizures (PTZ) test have provided data to develop PKPD models in mice for two compounds, rufinamide and drug X. For rufinamide, the preclinical PD markers were linked to the clinical outcome (loge seizure frequency). Then, the link function was applied to predict drug X PKPD relationship (clinical outcome) from the results of the same preclinical tests.
Results and conclusion: The PD markers were the percentage of protected mice against induced seizures for MES and PTZ tests. An Emax and sigmoid-Emax models were used to describe respectively the results to the PTZ and MES tests for the two drugs. Subsequently, a Weibull function was used to relate rufinamide preclinical results to rufinamide clinical PKPD model of the loge seizure frequency. Using this extrapolation model and the preclinical results for drug X, a prediction of the clinical outcome after drug X therapy was obtained at different levels of drug X concentration. Thereafter, the concentration-response relationship was identified and further used for the selection of optimal doses for future clinical studies in epilepsy with drug X.
Reference:
O. Petricoul, V. Cosson, C. Crepin, E. Fuseau, D. Critchley; Understanding the variability in clinical response to rufinamide, a new antiepileptic drug: a pooled PKPD analysis, PAGE 14 (2005) abstract 784.