Evaluating pharmacokinetic drug–drug interactions of direct oral anticoagulants in patients with renal dysfunction

ABSTRACT

Introduction

Drug transporters, metabolic enzymes, and renal clearance play significant roles in the pharmacokinetics of direct oral anticoagulants (DOACs). Recommendations for DOAC drug–drug interactions (DDIs) by the product labeling are limited to selected CYP3A4 and P-glycoprotein inhibitors and lack considerations for concomitant renal dysfunction.

Areas covered

This review focuses on: 1) current recommendations for the management of pharmacokinetic DOAC DDIs and the evidence used to support them; 2) alterations in DOAC exposure in the setting of concomitant DDIs and mild, moderate, and severe renal impairment; 3) clinical outcomes associated with this combination; and 4) expert recommendations for the management of pharmacokinetic DOAC DDIs. English-language, full-text articles on apixaban, dabigatran, rivaroxaban, and edoxaban with a publication date up to 30 September 2021 were retrieved from PubMed.

Expert opinion

Given the lack of supporting clinical data, empiric dose adjustments based on pharmacokinetic data alone should be avoided. When a considerable increase in a DOAC exposure is anticipated, it may be advisable to use an alternative DOAC or anticoagulant from a different class. Future research on identification of DOAC therapeutic ranges and target patient populations is needed to inform clinical utility of DOAC level monitoring to guide the management of DDIs.

KEYWORDS:

• Apixaban
• dabigatran
• drug interaction
• edoxaban
• renal impairment
• rivaroxaban

Article highlights

• The product labeling guidance for the management of direct oral anticoagulant (DOAC) drug–drug interactions (DDIs) is limited to specific CYP3A4 and P-glycoprotein inhibitors without assessment of clinical outcomes from clinical studies.

• Dose reductions based on renal function were evaluated in the clinical trials. However, moderate renal impairment was present in a minority of the patient population and those with severe renal impairment were generally excluded from the clinical trials.

• Unsurprisingly, the impact of concomitant DDIs and renal dysfunction on DOAC exposure has not been well described in clinical studies but has been assessed using physiologically based pharmacokinetic models. These models predict additive increase in DOAC exposure but may have the potential to overestimate this scenario.

• Clinical data on bleeding outcomes are desperately warranted to evaluate the impact of increased DOAC exposure in the setting of concomitant DDIs and renal dysfunction.

• Currently, DOAC drug levels are of limited utility for tailoring therapy but may be useful in assessing overexposure and risk stratification in the setting of concomitant DDIs and renal dysfunction.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.