Pharmacokinetics of dabigatran etexilate and rivaroxaban in patients with short bowel syndrome requiring parenteral nutrition: The PDER PAN study. Issue 160 (December 2017)

• Record Type: Journal Article
• Authors: Cheung, Y. Whitney; Barco, Stefano; Mathôt, Ron A.A.; van den Dool, Erik-Jan; Stroobants, An K.; Serlie, Mireille J.; Middeldorp, Saskia; Coppens, Michiel
• Is Part Of: Thrombosis research. Issue 160(2017)
• Page Start: 76
• Page End: 82
• Publication Date: 2017-12
• Subjects: Anticoagulants -- Short bowel syndrome -- Parenteral nutrition -- Pharmacokinetics -- Rivaroxaban -- Dabigatran etexilate; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2017.10.025
• Languages: English
• ISSNs: 0049-3848

Abstract

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 (AUC0 − t ) to reference values retrieved from phase I-III studies. Methods: We enrolled 6 adults with a remaining small bowel length ≤ 200 cm, normal renal/hepatic function, and intact stomach. In our crossover study, patients were exposed to twice-daily dabigatran etexilate 150 mg and once-daily rivaroxaban 20 mg. Results: After 5 days of dabigatran dosing, Ctrough and Cmax geometric means were 39 μg/L (90% CI: 23–66) and 88 μg/L (90% CI: 56–137), respectively; AUC0–12 h was 958 μg ∗ h/L (90% CI: 635–1445). After 5 days of rivaroxaban dosing, Ctrough and Cmax geometric means were 9 μg/L (90% CI: 1–71) and 167 μg/L (90% CI: 102–276), respectively; AUC0–24 h was 1720 μg ∗ h/L (90% CI: 899–3300). Absorption was negligible in one patient with ultra-short (~ 15 cm) 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 AUC0–24 h 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. Highlights: Patients on parenteral nutrition for short bowel syndrome (SBS) are at high thrombotic and bleeding risk Dabigatran and rivaroxaban pharmacokinetics parameters indicate lower absorption in SBS patients compared to non-SBS patients in phase III trials Rivaroxaban might be absorbed to a larger extent than dabigatran There is significant inter-individual variability in achieved plasma drug levels One patient with ultra-short remaining bowel showed negligible drug absorption of both drugs