(S-064) Physiologically Based Pharmacokinetic Modeling of Quizartinib to Assess Drug-Drug Interaction as an Inhibitor of Breast Cancer Resistance Protein
Akiko Watanabe: No financial relationships to disclose
Objectives: Quizartinib is an orally-administered, highly-potent type II FMS-like tyrosine kinase 3 inhibitor, indicated for the treatment of acute myeloid leukemia. In vitro study revealed that quizarinib has an inhibitory effect on breast cancer resistance protein (BCRP). The aim of this study is to develop a physiologically based pharmacokinetic (PBPK) model of quizartinib incorporating the inhibitory effect on BCRP and assess the drug-drug interaction (DDI) risk of quizartinib as an BCRP inhibitor.
Methods: The PBPK model of quizartinib was previously developed for the assessment of the inhibitory potential of UDP-glucuronosyltransferase 1A1 [1]. In this study, the model was updated in Simcyp Simulator V23.2 to evaluate the potential of quizartinib to inhibit BCRP. Unbound competitive inhibition constant (Ki,u) values of quizartinib for P-gp and BCRP were obtained by correcting a competitive inhibition constant (Ki) with the measured fraction unbound in the incubation media of the cell-based assay and then input into the PBPK model. The model was optimized and validated using clinical PK data after single oral- and multiple oral-dosing of quizartinib, human mass-balance data obtained following intravenous and oral administration of quizartinib [2]. In addition, the clinical DDI study with a P-gp substrate, dabigatran etexilate [2] was used in order to confirm whether an in vitro Ki,u value for an efflux transporter such as P-gp could recover the in vivo inhibitory potential. The validated PBPK model was applied to predict the effect of quizartinib on a BCRP substrate, rosuvastatin or sulfasalazine.
Results: The developed model reasonably recovered the PK of quizartinib. The PBPK model also sufficiently predicted the clinically observed DDI result with dabigatran etexilate which exhibited negligible DDI (1.13- and 1.11-fold increases in Cmax and AUC, respectively), suggesting that the in vitro Ki,u value allowed us to adequately predict the inhibitory effect of quizartinib on intestinal efflux transporters in vivo. The validated PBPK model predicted that oral multiple-dose co-administration of 60 mg quizartinib once a day would increase the Cmax and AUC by 3.31- and 2.44-fold, respectively, for rosuvastatin and by 2.66- and 2.66-fold, respectively, for sulfasalazine.
Conclusions: The PBPK model of quizartinib was adequately developed and validated to predict DDI with BCRP substrates based on the currently available datasets. The PBPK modeling results could inform that the impact of quizartinib on BCRP substrate would be moderate in the clinic.
Citations: [1] Ming Zheng et. al., Poster presentation in ACoP Annual Meeting 2022. [2] FDA review report: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216993Orig1s000MultidisciplineR.pdf
