title: Utility of CYP3A4 and PXR-CAR-CYP3A4/3A7 Transgenic Mouse Models To Assess the Magnitude of CYP3A4 Mediated Drug-Drug Interactions.
abstract: Species differences in the expression, activity, regulation, and substrate specificity of metabolizing enzymes preclude the use of animal models to predict clinical drug-drug interactions (DDIs). The objective of this work is to determine if the transgenic (Tg) Cyp3a-/-Tg-3A4Hep/Intand Nr1i2/Nr1i3-/--Cyp3a-/-Tg-PXR-CAR-3A4/3A7Hep/Int(PXR-CAR-CYP3A4/3A7) mouse models could be used to predict in vivo DDI of 10 drugs; alprazolam, bosutinib, crizotinib, dasatinib, gefitinib, ibrutinib, regorafenib, sorafenib, triazolam, and vandetinib (as victims); with varying magnitudes of reported CYP3A4 clinical DDI. As an assessment of the effect of CYP3A4 inhibition, these drugs were coadministered to Cyp3a-/-Tg-3A4Hep/Intmice with the CYP3A inhibitor, itraconazole. For crizotinib, regorafenib, sorafenib, and vandetanib, there was no significant increase of AUC observed; with alprazolam, bosutinib, ibrutinib, dasatinib, and triazolam, pretreatment with itraconazole resulted in a 2-, 4-, 17-, 7-, and 15-fold increase in AUC, respectively. With the exception of gefinitib for which the DDI effect was overpredicted (12-fold in Tg-mice vs 2-fold in the clinic), the magnitude of AUC increase observed in this study was consistent (within 2-fold) with the clinical DDI observed following administration with itraconazole/ketoconazole. As an assessment of CYP3A4 induction, following rifampin pretreatment to PXR-CAR-3A4/3A7Hep/Intmice, an 8% decrease in vandetanib mean AUC was observed; 39-52% reduction in AUC were observed for dasatinib, ibrutinib, regorafenib, and sorafenib compared to vehicle treated mice. The greatest effect of rifampin induction was observed with alprazolam, bosutinib, crizotinib, gefitinib, and triazolam where 72-91% decrease in AUC were observed. With the exception of vandetanib for which rifampin induction was under-predicted, the magnitude of induction observed in this study was consistent (within 2-fold) with clinical observations. These data sets suggest that, with two exceptions, these transgenic mice models were able to exclude or capture the magnitude of CYP3A4 clinical inhibition and induction. Data generated in transgenic mice may be used to gain confidence and complement in vitro and in silico methods for assessing DDI potential/liability.
authors.affiliation: Genentech Inc. , South San Francisco, California 94080, United States.
authors.forename: Justin Q
authors.initials: JQ
authors.lastname: Ly
authors.affiliation: Genentech Inc. , South San Francisco, California 94080, United States.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Messick
authors.affiliation: Genentech Inc. , South San Francisco, California 94080, United States.
authors.forename: Ann
authors.initials: A
authors.lastname: Qin
authors.affiliation: Genentech Inc. , South San Francisco, California 94080, United States.
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Takahashi
authors.affiliation: Genentech Inc. , South San Francisco, California 94080, United States.
authors.forename: Edna F
authors.identifier: 0000-0003-4200-8302
authors.initials: EF
authors.lastname: Choo
mesh_terms: D000525:Alprazolam / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D002853:Chromatography, Liquid; D000090702:Constitutive Androstane Receptor; D000077547:Crizotinib; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D000069439:Dasatinib / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000378:metabolism; D007654:Ketoconazole / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009570:Nitriles / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D011799:Quinazolines / Q000378:metabolism; D011804:Quinolines / Q000378:metabolism; D012293:Rifampin / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014229:Triazolam / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; D009570:Nitriles; C000716328:Nr1i3 protein, mouse; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D011804:Quinolines; D014229:Triazolam; D017964:Itraconazole; C471992:bosutinib; D000077547:Crizotinib; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole; D000069439:Dasatinib; D012293:Rifampin; C452423:vandetanib; D000525:Alprazolam
keywords: CYP3A4; drug−drug interaction; transgenic mouse model