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Quantitative evaluation of the combination between cytotoxic drug and efflux transporter inhibitors based on a tumour growth inhibition model
Author(s) -
Sostelly Alexandre,
Payen Léa,
Guitton Jérôme,
Pietro Attilio Di,
Falson Pierre,
Honorat Mylène,
Boumendjel Ahcène,
Gèze Annabelle,
Freyer Gilles,
Tod Michel
Publication year - 2014
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/fcp.12005
Subject(s) - irinotecan , efflux , pharmacology , transporter , atp binding cassette transporter , chemistry , drug , in vivo , pharmacokinetics , biology , medicine , biochemistry , cancer , colorectal cancer , gene , microbiology and biotechnology
ATP ‐Binding Cassette transporters such as ABCG 2 confer resistance to various anticancer drugs including irinotecan and its active metabolite, SN 38. Early quantitative evaluation of efflux transporter inhibitors‐cytotoxic combination requires quantitative drug‐disease models. A proof‐of‐concept study has been carried out for studying the effect of a new ABCG 2 transporter inhibitor, MBLI 87 combined to irinotecan in mice xenografted with cells overexpressing ABCG 2. Mice were treated with irinotecan alone or combined to MBLI 87, and tumour size was periodically measured. To model those data, a tumour growth inhibition model was developed. Unperturbed tumour growth was modelled using Simeoni's model. Drug effect kinetics was accounted for by a Kinetic–Pharmacodynamic approach. Effect of inhibitor was described with a pharmacodynamic interaction model where inhibitor enhances activity of cytotoxic. This model correctly predicted tumour growth dynamics from our study. MBLI 87 increased irinotecan potency by 20% per μmol of MBLI 87. This model retains enough complexity to simultaneously describe tumour growth and effect of this type of drug combination. It can thus be used as a template to early evaluate efflux transporter inhibitors in‐vivo .