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

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 <= 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 mu g/L (90% CI: 23-66) and 88 mu g/L (90% CI: 56-137), respectively; AUC(0-12) h was 958 mu g*h/L (90% CI: 635-1445). After 5 days of rivaroxaban dosing, Ctrough and Cmax geometric means were 9 mu g/L (90% CI: 1-71) and 167 mu g/L (90% CI: 102-276), respectively; AUC(0-24) h was 1720 mu g*h/L (90% CI: 899-3300). Absorption was negligible in one patient with ultra-short (similar to 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 AUC(0-24) 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