Potential Underprediction of Warfarin Drug Interaction From Conventional Interaction Studies and Risk Mitigation: A Case Study With Epacadostat, an IDO1 Inhibitor

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...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2016-11, Vol.56 (11), p.1344-1354
Main Authors: Shi, Jack G., Chen, Xuejun, Punwani, Naresh G., Williams, William V., Yeleswaram, Swamy
Format: Article
Language:English
Subjects:
Adult
Anticoagulants - blood
Anticoagulants - pharmacology
Cross-Over Studies
Drug Interactions - physiology
drug-drug interaction (DDI)
epacadostat
Female
Forecasting
Humans
IDO
Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors
INR
International Normalized Ratio - methods
Male
Middle Aged
Oximes - blood
Oximes - pharmacology
Risk Factors
Sulfonamides - blood
Sulfonamides - pharmacology
warfarin
Warfarin - blood
Warfarin - pharmacology
Young Adult
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Summary: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.
ISSN:0091-2700
1552-4604
DOI:10.1002/jcph.737