Pharmacokinetics of dabigatran etexilate and rivaroxaban in patients with short bowel syndrome requiring parenteral nutrition: The PDER PAN study

Y Whitney Cheung; Stefano Barco; Ron A A Mathôt; Erik-Jan van den Dool; An K Stroobants; Mireille J Serlie; Saskia Middeldorp; Michiel Coppens

doi:10.1016/j.thromres.2017.10.025

Pharmacokinetics of dabigatran etexilate and rivaroxaban in patients with short bowel syndrome requiring parenteral nutrition: The PDER PAN study

Thromb Res. 2017 Dec:160:76-82. doi: 10.1016/j.thromres.2017.10.025. Epub 2017 Nov 4.

Authors

Y Whitney Cheung¹, Stefano Barco², Ron A A Mathôt³, Erik-Jan van den Dool⁴, An K Stroobants⁴, Mireille J Serlie⁵, Saskia Middeldorp¹, Michiel Coppens¹

Affiliations

¹ Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
² Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center for Thrombosis and Hemostasis, University Medical Hospital of the Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address: s.barco@uni-mainz.de.
³ Hospital Pharmacy-Clinical Pharmacology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
⁴ Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
⁵ Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

PMID: 29127863
DOI: 10.1016/j.thromres.2017.10.025

Abstract

Background and aims: Patients on parenteral nutrition for short bowel syndrome (SBS) have a high risk of thrombotic complications and are often treated with parenteral anticoagulation. Direct oral anticoagulants are absorbed proximally in the digestive tract and may represent alternative regimens in selected SBS patients. In our pilot study, we provided pharmacokinetics parameters of dabigatran etexilate and rivaroxaban in this setting and compared peak (Cmax), trough (Ctrough) concentrations, and areas-under-the-concentration-time-curve (AUC_0-t) to reference values retrieved from phase I-III studies.

Methods: We enrolled 6 adults with a remaining small bowel length≤200cm, normal renal/hepatic function, and intact stomach. In our crossover study, patients were exposed to twice-daily dabigatran etexilate 150mg and once-daily rivaroxaban 20mg.

Results: After 5days of dabigatran dosing, Ctrough and Cmax geometric means were 39μg/L (90% CI: 23-66) and 88μg/L (90% CI: 56-137), respectively; AUC_0-12h was 958μg∗h/L (90% CI: 635-1445). After 5days of rivaroxaban dosing, Ctrough and Cmax geometric means were 9μg/L (90% CI: 1-71) and 167μg/L (90% CI: 102-276), respectively; AUC_0-24h was 1720μg∗h/L (90% CI: 899-3300). Absorption was negligible in one patient with ultra-short (~15cm) bowel. For dabigatran, Cmax ratio was 0.57 (SD 0.33) and Ctrough ratio was 0.35 (SD 0.44). For rivaroxaban, the mean observed-to-reference ratios AUC_0-24h and Cmax ratios were 0.73 (SD 0.32) and 0.76 (SD 0.34), respectively.

Conclusions: While in SBS patients there is some absorption of the oral anticoagulants dabigatran etexilate and rivaroxaban, it appears to be lower than reference values. Plasma drug levels showed significant inter-individual variability.

Keywords: Anticoagulants; Dabigatran etexilate; Parenteral nutrition; Pharmacokinetics; Rivaroxaban; Short bowel syndrome.

MeSH terms

Adult
Aged
Antithrombins / pharmacokinetics
Antithrombins / therapeutic use*
Dabigatran / pharmacokinetics
Dabigatran / therapeutic use*
Female
Humans
Male
Middle Aged
Parenteral Nutrition / methods*
Rivaroxaban / pharmacokinetics
Rivaroxaban / therapeutic use*
Short Bowel Syndrome / drug therapy*
Short Bowel Syndrome / pathology

Substances

Antithrombins
Rivaroxaban
Dabigatran