P86 IN VITRO CHARACTERIZATION OF DRUG METABOLIZING ENZYMES AND TRANSPORTERS TO ENABLE A MECHANISTIC DRUG-DRUG INTERACTION ASSESSMENT FOR VENETOCLAX

Ryota Kikuchi , AbbVie Inc., North Chicago, IL
Mohamad Shebley , Dmpk-BA, AbbVie Inc., North Chicago, IL
Daniel A.J. Bow , AbbVie Inc., North Chicago, IL
Robert A Carr , AbbVie Inc., North Chicago, IL
Marjoleen Nijsen , Dmpk-BA, AbbVie Inc., North Chicago, IL
Sonia M de Morais , AbbVie Inc., North Chicago, IL
In vitro tools were used to characterize the drug-drug interaction (DDI) potential for venetoclax (ABT-199) and its human major metabolite M27 as victims or perpetrators of Cytochrome P450 (CYP), Uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes and drug transporters.  Venetoclax and M27 were predominantly metabolized by CYP3A4, while UGTs were not involved in the metabolism.  Both venetoclax and M27 were identified as substrates for the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) but not for hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3 or organic cation transporter (OCT) 1.  The nonclinical predictions for venetoclax were consistent with the clinical findings observed with ketoconazole (CYP3A4/P-gp inhibitor) and rifampin (CYP3A4/P-gp inducer).  Venetoclax PBPK model simulations were consistent with results from the clinical ketoconazole and rifampin studies: predicted vs observed ratios for venetoclax Cmax and AUC were within 0.8-1.25 fold.  At a 400 mg dose, venetoclax and M27 are not predicted to inhibit CYPs but venetoclax may weakly inhibit UGT1A1 (predicted AUCR 1.38) based on the mechanistic static model.  Venetoclax and M27 are P-gp and BCRP inhibitors with IC50 values of 0.79 and 0.13 µM (venetoclax) and 0.83 and 1.48 µM (M27), respectively, and at clinically relevant exposures may inhibit these transporters ([I]2/IC50 >10 and [I]1/IC50 >0.1).  Venetoclax is an OATP1B1 inhibitor (IC50 10.1 µM in the presence of 4% bovine serum albumin) and an R-total value of 1.33 (calculated using total plasma exposure) indicates that venetoclax may interact with drugs that are substrates for this transporter.  No interaction with other transporters (OATP1B3, OCT1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion protein (MATE) 1 or MATE2K) was predicted.  Overall, an in vitro characterization of drug metabolizing enzyme and transporters enabled a mechanistic assessment of DDI potential for venetoclax.

Disclosures: All authors are employees of AbbVie.  The design, study conduct, and financial support for this research was provided by AbbVie.  AbbVie participated in the interpretation of data, review, and approval of the publication.