Pharmacokinetics and –dynamics of Dabigatran Etexilate and Rivaroxaban in patients requiring PArenteral Nutrition (the PDER PAN study)

Chronic intestinal failure (IF) is caused by either surgically induced anatomical short bowel, severe motility, or absorption disorders. These patients require partial or total parenteral nutrition (PN and TPN, respectively) and are thereby critically dependent on maintaining venous access with a central venous catheter (CVC). Recurrent CVC-related thrombosis will ultimately lead to loss of central venous access with intestinal transplantation being the only treatment option left. Therefore, patients at risk for recurrent thrombosis and requiring (T)PN are often treated with long-term anticoagulants to prevent CVC-thrombosis, such as INR-adjusted vitamin K antagonists (VKAs) or low-molecular-weght heparins (LMWHs).
A new generation of oral anticoagulants (NOACs), including dabigatran etexilate and rivaroxaban, has recently been approved for several indications. In contrast with VKAs, these drugs do not interact with vitamin K metabolism, have a more predictable pharmacokinetic profile, have less interaction with other drugs, and are prescribed at a fixed dose without routine laboratory monitoring. Importantly, these drugs are absorbed proximally in the gastrointestinal tract (stomach, duodenum, and proximal small bowel). Therefore, NOACs may be an attractive oral alternative to both LMWH injections and VKAs in these patients.
The aim of the PDER PAN phase I study is to assess the extent of intestinal absorption of rivaroxaban 20 mg once-daily and dabigatran etexilate 150 mg twice-daily at steady state in adult patients with short bowel syndrome requiring long-term TPN.
The primary outcome is the assessment of pharmacokinetics and -dynamics parameters of the two drugs, and the comparison to published values from studies in healthy volunteer.

The aim of this phase I study is to assess the extent of intestinal absorption of rivaroxaban and dabigatran etexilate in adult patients with short bowel syndrome requiring long-term TPN.

Blood samples will be collected at the research unit at the following times:

1) after rivaroxaban administration:

- Day 0: T = 0 (= blank), T = 3 hours following the first dose;

- Day 4 at steady state: T = 0 (= trough), T = 1, 2, 3, 4, 5, 6, 8, 10, 24 hour(s) following the fifth dose.

2) after dabigatran etexilate administration:

- Day 0: T = 0 (= blank), T = 3 hours following the first dose;

- Day 4 at steady state: T = 0 (= trough), T = 1, 2, 3, 4, 5, 6, 8, 12 hour(s) following the ninth dose.

In a cross-over design, patients will be treated with either rivaroxaban 20 mg once daily for five days or dabigatran etexilate 150 mg twice daily for five days. Between the two treatment periods, a wash out period of at least 4 days will be applied. After each 5-day period of NOAC use, patients will be admitted for a full pharmacokinetic and –dynamic profile will be obtained with 10 blood samples.