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AAPS J. 2017 Mar;19(2):497-509. doi: 10.1208/s12248-016-0021-0. Epub 2016 Dec 6.

A Model for Predicting the Interindividual Variability of Drug-Drug Interactions.

Tod M1,2,3, Bourguignon L4,5,6, Bleyzac N7,8, Goutelle S4,5,6.

Author information

1
Pharmacie, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France. michel.tod@univ-lyon1.fr.
2
EMR3738, Faculté de médecine Lyon-sud, Université Lyon 1, Lyon, France. michel.tod@univ-lyon1.fr.
3
Faculté de pharmacie, Université Lyon 1, Lyon, France. michel.tod@univ-lyon1.fr.
4
Pharmacie, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France.
5
Faculté de pharmacie, Université Lyon 1, Lyon, France.
6
UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Université Lyon 1, Lyon, France.
7
EMR3738, Faculté de médecine Lyon-sud, Université Lyon 1, Lyon, France.
8
Pharmacie, Institut d'Hématologie et d'Oncologie Pédiatrique, Hospices Civils de Lyon, Lyon, France.

Abstract

Pharmacokinetic drug-drug interactions are frequently characterized and quantified by an AUC ratio (Rauc). The typical value of the AUC ratio in case of cytochrome-mediated interactions may be predicted by several approaches, based on in vitro or in vivo data. Prediction of the interindividual variability of Rauc would help to anticipate more completely the consequences of a drug-drug interaction. We propose and evaluate a simple approach for predicting the standard deviation (sd) of Ln(Rauc), a metric close to the interindividual coefficient of variation of Rauc. First, a model was derived to link sd(Ln Rauc) with the substrate fraction metabolized by each cytochrome and the potency of the interactors, in case of induction or inhibition. Second, the parameters involved in these equations were estimated by a Bayesian hierarchical model, using the data from 56 interaction studies retrieved from the literature. Third, the model was evaluated by several metrics based on the fold prediction error (PE) of sd(Ln Rauc). The median PE was 0.998 (the ideal value is 1) and the interquartile range was 0.96-1.03. The PE was in the acceptable interval (0.5 to 2) in 52 cases out of 56. Fourth, a surface plot of sd(Ln Rauc) as a function of the characteristics of the substrate and the interactor has been built. The minimal value of sd(Ln Rauc) was about 0.08 (obtained for Rauc = 1) while the maximal value, 0.7, was obtained for interactions involving highly metabolized substrates with strong interactors.

KEYWORDS:

cytochromes; drug interactions; interindividual variability; pharmacokinetics; prediction model

PMID:
27924615
DOI:
10.1208/s12248-016-0021-0
[Indexed for MEDLINE]

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