title: Potential Underprediction of Warfarin Drug Interaction From Conventional Interaction Studies and Risk Mitigation: A Case Study With Epacadostat, an IDO1 Inhibitor.
abstract: Drug-drug interaction (DDI) studies involving warfarin are typically conducted with subtherapeutic doses of warfarin to ensure the safety of volunteers. However, this approach may potentially have a systemic bias of underestimating pharmacodynamic (PD) DDI effect on warfarin at therapeutic levels of anticoagulation. We demonstrate here the utility of model-based DDI prediction for a clinically relevant warfarin regimen, using the example of epacadostat (INCB024360), the first-in-class indoleamine 2,3-dioxygenase 1 inhibitor in clinical development as a novel orally active immuno-oncological therapy. Observed data from a dedicated clinical DDI study using subtherapeutic warfarin suggested warfarin pharmacokinetics (PK), but not PD (anticoagulation), was significantly affected by concomitant epacadostat. However, subsequent PK/PD modeling and simulations indicated a clinically important DDI effect on warfarin PD at a higher baseline of the international normalization ratio (INR) and enabled recommendation of warfarin dose adjustment that is dependent on epacadostat dosing regimen and target INR.
authors.affiliation: Incyte Corporation, Wilmington, DE, USA. jshi@incyte.com.
authors.forename: Jack G
authors.initials: JG
authors.lastname: Shi
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Chen
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.
authors.forename: Naresh G
authors.initials: NG
authors.lastname: Punwani
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.
authors.forename: William V
authors.initials: WV
authors.lastname: Williams
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000097:blood* / Q000494:pharmacology; D018592:Cross-Over Studies; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D005544:Forecasting; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D019934:International Normalized Ratio / Q000379:methods; D008297:Male; D008875:Middle Aged; D010091:Oximes / Q000097:blood* / Q000494:pharmacology; D012307:Risk Factors; D013449:Sulfonamides / Q000097:blood* / Q000494:pharmacology; D014859:Warfarin / Q000097:blood* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000925:Anticoagulants; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D010091:Oximes; D013449:Sulfonamides; D014859:Warfarin; C000613752:epacadostat
keywords: IDO; INR; drug-drug interaction (DDI); epacadostat; warfarin