Michel Tod (1), Philippe B. Pierrillas (1), Laurent Bourguigon (2) and Sylvain Goutelle (2)
(1) EMR3738, Université Lyon 1, France, (2) UMR CNRS5558, Université Lyon 1, France
Objectives: Quantitative prediction of the magnitude of a drug-drug interaction (DDI) is useful to identify the clinical interaction studies to be performed during drug development, and the dosing adaptation to be made in the context of drug prescription. Two approaches for quantitative prediction of DDIs mediated by inhibition or induction of cytochromes are the Mechanistic Dynamic interaction Model (MDM) based on in vitro data plugged into a physiologically-based pharmacokinetic model [1], and the Mechanistic Static interaction Model based on in vivo data (IMSM) [2]. The aim of this study was to evaluate the performance of IMSM and to compare IMSM with the MDM approach.
Methods: The magnitude of a pharmacokinetic interaction is usually expressed as the ratio of the victim drug AUC given in combination with an interacting drug (i.e. inducer or inhibitor) to the victim drug AUC given alone. The predictive performances of IMSM (implemented in www.ddi-predictor.org) were evaluated on a panel of 628 clinical sudies of DDIs. The predictive performances of IMSM and MDM (implemented in Simcyp software) were compared on a set of 104 clinical sudies of DDIs. The metrics is the fold prediction error, i.e. the predicted AUC ratio / observed AUC ratio.
Results: On the 628 DDIs panel, the IMSM yielded 85% of predictions within 1.5 fold of the observed value. On the 104 DDIs panel, the predictive performances of IMSM were better than those of MDM : median fold error 1 versus 0.86 (p = 0.02), interquartile fold error 0.40 versus 0.52 respectively.
Conclusion: The IMSM approach is a quick, inexpensive and simple alternative for the prediction of metabolic interactions mediated by cytochromes. It may be of interest for both drug development and management of DDIs in clinical practice. The IMSM approach works correctly if cytochromes are the main interaction mechanism, and the kinetics of the substrate is (at least approximately) linear. The MDM approach remains the best approach for the prediction of DDIs involving transporters, provided that the PBPK model is correctly specified.
References:
[1] Einolf HJ. Comparison of different approaches to predict metabolic drug-drug interactions. Xenobiotica, 37(10-11), 1257-1294 (2007).
[2] Tod M, Nkoud-Mongo C, Gueyffier F. Impact of genetic polymorphism on drug-drug interactions mediated by cytochromes: a general approach. AAPS J, 15(4), 1242-1252 (2013).
Reference: PAGE 25 (2016) Abstr 3695 [www.page-meeting.org/?abstract=3695]
Poster: Methodology - New Modelling Approaches