The Impact of Strong Inducers on Direct Oral Anticoagulant Levels - 28/09/21

Doi : 10.1016/j.amjmed.2021.06.003

Anne-Laure Sennesael, MPharm, MSc, PhD ^a,^b,^⁎ , Anne-Sophie Larock, MPharm, MSc ^a, Philippe Hainaut, MD, PhD ^c, Sarah Lessire, MD, PhD ^d, Michael Hardy, MD ^d,^e, Jonathan Douxfils, MPharm, PhD ^f,^g, Anne Spinewine, MPharm, MSc, PhD ^a,^b, François Mullier, MPharm, MSc, PhD ^e
^a Department of Pharmacy, Centre Hospitalier Universitaire (CHU) UCL Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Université catholique de Louvain, Yvoir, Belgium
^b Clinical Pharmacy Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
^c Department of Internal Medicine, Cliniques Universitaires Saint-Luc, Brussels, Université catholique de Louvain, Belgium
^d Department of Anesthesiology, CHU UCL Namur, NTHC, NARILIS, Université catholique de Louvain, Yvoir, Belgium
^e Hematology Laboratory, CHU UCL Namur, NTHC, NARILIS, Université catholique de Louvain, Yvoir, Belgium
^f Department of Pharmacy, NTHC, NARILIS, Université de Namur, Namur, Belgium
^g Qualiblood s.a., Namur, Belgium

^⁎Requests for reprints should be addressed to Anne-Laure Sennesael, MPharm, MSc, PhD, Department of Pharmacy, Université catholique de Louvain, CHU UCL Namur, Av Dr G. Therasse 1, 5530 Yvoir, Belgium.Department of PharmacyUniversité catholique de Louvain, CHU UCL NamurAv Dr G. Therasse 1Yvoir5530Belgium

Abstract

Purpose

The concomitant use of direct oral anticoagulants (DOAC) and strong P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) inducers may lead to reduced DOAC levels and therapeutic failure. This study aimed to describe DOAC concentrations in patients receiving strong P-gp and CYP3A4 inducers, in relation to individual risk factors for high or low DOAC levels.

Methods

We retrospectively identified hospitalized patients simultaneously receiving a DOAC and carbamazepine, phenobarbital, phenytoin, or rifampicin between 2016 and 2021. Among them, patients who underwent DOAC measurement at steady state were included. DOAC peak or trough levels were compared with on-therapy ranges observed in pivotal trials. Individual risk factors for high or low DOAC levels were identified.

Results

We included 17 patients (median age 75 years), mainly receiving apixaban and carbamazepine. For 5 patients (29%), DOAC trough or peak level was below the expected range. Among the remaining 12 patients, 8 had at least one measurement in the lower quartile of the range. The median number of risk factors for drug accumulation was 0 (range 0-1) in patients with ≥1 measurement below the range and 2 (range 0-3) in other patients. DOAC measurement led to treatment adjustments in 9 patients (DOAC dose increase or switch).

Conclusion

Our data suggest a significant risk of reduced DOAC levels in patients taking strong P-gp and CYP3A4 inducers, especially those without risk factors for drug accumulation. DOAC measurement could help manage this relevant drug–drug interaction.

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Keywords : Direct oral anticoagulants, Drug–drug interactions, Laboratory measurement

Esquema

	Funding: Fondation Mont-Godinne, Yvoir, Belgium.
	Conflicts of Interest: JD is the CEO and founder of QUALIblood s.a., a Belgian Contract Research Organization, and reports personal fees from Daiichi-Sankyo, DOASense, Mithra Pharmaceuticals, Norgine, Portola, Stago, Roche, and Roche Diagnostics outside the submitted work. FM reports institutional fees from Stago, Werfen, Nodia, Roche Sysmex, and Bayer, all outside the submitted work. FM also reports speaker fees from Boehringer Ingelheim, Bayer Healthcare, Bristol-Myers Squibb-Pfizer, Stago, Sysmex, Werfen, and Aspen, all outside the submitted work.
	Authorship: All authors had access to the data and a role in writing the manuscript.