Characterization of the interaction between irinotecan, SN-38 and MBLI-87, a new BCRP inhibitor, with a multi-scale semi-mechanistic PKPD model
Alexandre Sostelly (1,2), Léa Payen (3,4,5), Jérôme Guitton (1,3,5), Ahcène Boumendjel (6), Attilio Di Pietro (7), Pierre Falson (7), Gilles Freyer (1,2,5), Michel Tod (1,3,5)
(1) EMR3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Lyon France; (2) Université de Lyon, Lyon France; (3) Institut des Sciences Pharmaceutiques et Biologiques, Lyon France; (4) INSERM U590, Centre Léon Bérard FNCLCC, Lyon France; (5) Hospices Civils de Lyon, Lyon France; (6) Département de Pharmacochimie Moléculaire UMR5063 CNRS/Université Joseph FOURIER, Grenoble France; (7) Equipe labellisée Ligue 2009, Institut de Biologie et Chimie de Protéines, UMR5086 CNRS/UCBL, IFR128 BioSciences Gerland-Lyon Sud, Lyon France
Background: Breast Cancer Resistance Protein (BCRP) confers resistance to irinotecan (CPT11) and its active metabolite, SN38. MBLI87, a new BCRP inhibitor, has proven its efficacy in-vitro and in-vivo against BCRP-mediated resistance1,2. We aimed at characterizing the 2 levels of interaction, intracellular and pharmacodynamic, between CPT11, SN38 and MBLI87 with a semi-mechanistic PKPD model to find key factors for treatment efficacy.
Methods: Plasmatic drugs disposition was evaluated in mice after single administration of CPT11 or MBLI87. Tumor growth data were issued from 2 proof-of-concept studies (POC1, POC2) where xenografted mice received vehicle or CPT11 or CPT11+MBLI87. Tumor size was repetitively measured during 40 days. Treatment intensity and delay between tumors implantation and 1st drug administration were greater in POC2.
Plasma drug kinetics was modeled using a compartmental approach. Natural tumor growth was described with Simeoni model3.
The 1st level of interaction was integrated in an intracellular drug disposition model: a mechanistic model was developed on in-vitro data to quantify CPT11, SN38 BCRP-affinity constants (Km), MBLI87 BCRP-inhibitory constant (Ki) and importance of active efflux4.
The 2nd interaction model consisted in CPT11 and SN38 cooperative interaction on tumor growth characterized by a semi-mechanistic pharmacodynamic model derived from Greco5.
The 4 submodels were combined and fitted separately on POC1 and POC2 to find key factors for treatment efficacy according to dosing regimens.
Results: Based on plasma concentrations, no plasma-PK interaction was found between the 3 compounds. Intracellular-PK interaction between CPT11, SN38 and MBLI87 was better described by a competitive interaction. BCRP-affinity was greater for SN38 than for CPT11, MBLI87 inhibitory constant was estimated at 2.5 µM.
In-vitro Km and Ki were corrected to take into account plasma protein binding. Active efflux was greater for SN38 and in POC2 study whereas CPT11 and SN38 cytotoxic potencies were in the same range in POC1 and POC2.
Despite greater treatment intensity in POC2, tumor shrinkage was greater in POC1 indicating that tumor access is a key factor for treatment efficacy.
Conclusions: This complex model including 2 levels of interaction was successfully applied to proof-of-concept data and allowed to point out key factors for treatment efficacy. MBLI87 is under further development, this model will be useful to guide its next development steps.
 Boumendjel A et al. Acridone derivatives: design, synthesis, and inhibition of breast cancer resistance protein ABCG2. BioOrg Med Chem. 2007
 Arnaud O et al. The acridone derivative MBLI-87 sensitizes breast cancer resistance protein-expressing xenografts to irinotecan. Eur J Cancer. 2010
 Simeoni M et al. Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth kinetics in xenograft models after administration of anticancer agents. Cancer Res. 2004
 Sostelly A et al. Intracellular penetration modeling of CPT11 in presence of efflux transporter inhibitors. 13e journée du GPCO [http://www.gpco.fr]
 Greco WR et al. The search for synergy: a critical review from a response surface perspective. Pharmacol Rev. 1995