PII-173 - LEVERAGING PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING AND CLINICAL DATA TO PREDICT DRUG-DRUG INTERACTIONS (DDI) OF AVAPRITINIB AND GUIDE DOSE ADJUSTMENTS.

A. Suram¹, J. Powers¹, N. Dave², S. Kim³, J. Baker¹, W. Ankrom¹; ¹Blueprint Medicines Corporation, Cambridge, MA, , ²LAPIX Therapeutics, Boston, MA, , ³IDRx, Inc., Plymouth, MA.

Background: Avapritinib, a KIT D816V and platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation inhibitor, is FDA-approved for the treatment of adult patients with unresectable/metastatic gastrointestinal stromal tumors harboring a PDGFRA exon 18 mutation and for patients with advanced or indolent systemic mastocytosis. Avapritinib undergoes extensive Phase 1 metabolism, predominantly by CYP3A4 and CYP3A5 enzymes; thus, avapritinib pharmacokinetics are predicted to be altered by strong CYP3A inducers or inhibitors. A previous clinical study in healthy volunteers (Study BLU-285-0104) showed significant DDI with a single dose of avapritinib when co-administered with itraconazole (a strong CYP3A inhibitor), leading to 40% and 320% increases in Cmax and AUC(0-inf), and rifampin (a strong CYP3A inducer), leading to 74% and 92% decreases in Cmax and AUC(0-inf). A PBPK model incorporating these findings was used to predict the magnitude of avapritinib’s DDIs at steady-state exposures in the target patient population to inform dose adjustment recommendations.

Methods: A PBPK model was used to simulate change in avapritinib steady state plasma exposure following single or repeat 300 mg avapritinib dosing in the presence of weak, moderate, and strong CYP3A inhibitors and inducers. Observed data were derived from single-dose administration (Study BLU-285-0104) and steady state plasma exposures were predicted. The model incorporated in vitro parameters from CYP3A4 inhibition by avapritinib and its metabolite M499, as well as CYP3A induction by avapritinib.

Results: PBPK simulations predicted a significant change in steady state avapritinib plasma exposure when co-administered with strong (itraconazole) and moderate (fluconazole) CYP3A inhibitors, with AUC(tau) increased >500% and 205%, respectively. A minimal change in plasma exposure was predicted with a weak CYP3A inhibitor (cimetidine) with < 25% increase in AUC(tau). Simulations with the moderate CYP3A inducer (efavirenz) predicted a 62% reduction in avapritinib exposure.

Conclusion: Based on these findings, it is recommended that avapritinib should not be co-administered with strong and moderate CYP3A inhibitors or inducers. If concomitant use of a moderate CYP3A inhibitor cannot be avoided, a reduction in dose is advised.