Anticoagulation, Short Bowel Syndrome
Conditions
Keywords
Apixaban, Pharmacokinetics
Brief summary
Short bowel syndrome (SBS) is defined as a loss of function of the small intestine resulting in a malabsorptive disorder. In SBS, oral drug absorption may be altered due to extensive intestinal resection. It remains unclear to what extent apixaban exposure is impacted in SBS.Therefore this study tries to investigate the pharmacokinetics (PK) of apixaban in adult patients with SBS requiring long-term parenteral nutrition (PN).
Interventions
DRUGApixaban single dose
A single dose of apixaban 2.5 mg and 5 mg (wash out period of at least 7 days) will be administered and PK characteristics will be measured
DRUGApixaban steady-state
Steady-state apixaban PK characteristics will be measured in patients already treated with apixaban
Sponsors
Universitaire Ziekenhuizen KU Leuven
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Interventional, non-randomized, open label, monocentric controlled study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
SBS single dose: \- patients with SBS (small bowel length of \<2m after Treitz ligament) on long term (\>3 months) PN or fluids who are apixaban-, vitamin K antagonist- and teduglutide naive Inclusion criteria SBS steady-state: \- patients with SBS (small bowel length of \<2m after Treitz ligament) on long term (\>3 months) PN or fluids who are teduglutide naive and who are already taking apixaban 2,5 mg or 5 mg twice daily for ≥ 4 days Inclusion criteria non-SBS single dose: \- healthy individuals without history of GI resections or other conditions associated with impaired absorption, who are apixaban- and vitamin K antagonist naive Inclusion criteria non-SBS steady-state: \- patients without history of gastrointestinal resections or other conditions associated with impaired absorption (= controls), who are already taking apixaban 2,5 mg or 5 mg twice daily for ≥ 4 days
Exclusion criteria
SBS (single dose+ steady-state): * \<18 years * non-Dutch speaking * recent (\<6 months) major bleeds according with the International Society on Thrombosis and Haemostasis definition of major bleeding in non-surgical patients (20) * creatinine clearance of \< 15 mL/min or dialysis dependent * liver failure classified as Child Pugh C * total bilirubin ≥ 1.77 mg/dL (= 1,5 x upper limit of normal) * presence of coagulopathy and a clinically relevant bleeding risk * pregnancy or lactation * concomitant intake of strong combined inhibitors of CYP3A4 and P-gp * participation in a recent (\<1 month) trial with an investigational product * recent (\<6 months) gastrointestinal surgery * gastrointestinal mucosal disease interfering with absorption (e.g. radio-enteritis, inflammatory bowel disease, celiac disease, …) * gastrointestinal fistulae * SBS with intestinal failure resulting from gastric bypass surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Cmax of apixaban between SBS and patients with a normal gastrointestinal tract | Through study completion, an average of 1.5 years | To investigate the difference in peak level (Cmax) after two different single dose administrations (2,5 mg and 5 mg) of apixaban between patients with and without SBS requiring long-term PN |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in time to reach Cmax (Tmax) of apixaban between SBS patients and patients with a normal gastrointestinal tract | Through study completion, an average of 1.5 years | To investigate differences in Tmax after two different single dose administrations (2,5 mg and 5 mg) of apixaban between patients with and without SBS requiring long-term PN |
| Difference in exposure (AUC0-12h) of apixaban between SBS patients and patients with a normal gastrointestinal tract | Through study completion, an average of 1.5 years | To investigate differences in AUC0-12 after two different single dose administrations (2,5 mg and 5 mg) of apixaban between patients with and without SBS requiring long-term PN |
| Difference in absorption rate constant of apixaban between SBS patients and patients with a normal gastrointestinal tract | Through study completion, an average of 1.5 years | To investigate the difference in absorption rate constant between patients with and without SBS requiring long-term PN |
| Difference in bioavailability of apixaban between SBS patients and patients with a normal gastrointestinal tract | Through study completion, an average of 1.5 years | To investigate the difference in bioavailability between patients with and without SBS requiring long-term PN |
| Difference in volume of distribution of apixaban between SBS patients and patients with a normal gastrointestinal tract | Through study completion, an average of 1.5 years | To investigate the difference in volume of distribution between patients with and without SBS requiring long-term PN |
| Difference in clearance of apixaban between SBS patients and patients with a normal gastrointestinal tract | Through study completion, an average of 1.5 years | To investigate the difference in clearance between patients with and without SBS requiring long-term PN |
| Difference in half-life of apixaban between SBS patients and patients with a normal gastrointestinal tract | Through study completion, an average of 1.5 years | To investigate the difference in half-life between patients with and without SBS requiring long-term PN |
| To set up an optimized dosing scheme of apixaban for SBS patients | Through study completion, an average of 1.5 years | To set up an optimized dosing scheme of apixaban, using PK modeling, for SBS patients taking into account identified covariates (eg. sex, age, race...) and PK measurements from outcome 1-9. |
| Difference in Cmax between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | To investigate the difference in Cmax between SBS patients with and without teduglutide |
| Difference in estimated trough level (Cmin) of apixaban between SBS and patients with a normal gastrointestinal tract | Through study completion, an average of 1.5 years | To investigate differences in estimated Cmin (12h after administration) after two different single dose administrations (2,5 mg and 5 mg) of apixaban between patients with and without SBS requiring long-term PN |
| Difference in Tmax between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | To investigate the difference in Tmax between SBS patients with and without teduglutide |
| Difference in AUC SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | To investigate the difference in Cmax, Cmin, Tmax, AUC, absorption rate constant, bioavailability, volume of distribution, clearance and half-life between SBS patients with and without teduglutide |
| Difference in AUC between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | To investigate the difference in Cmax, Cmin, Tmax, AUC, absorption rate constant, bioavailability, volume of distribution, clearance and half-life between SBS patients with and without teduglutide |
| Difference in absorption rate constant between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | To investigate the difference in absorption rate constant between SBS patients with and without teduglutide |
| Difference in bioavailability between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | To investigate the difference in bioavailability between SBS patients with and without teduglutide |
| Difference in volume of distribution between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | To investigate the difference in volume of distribution between SBS patients with and without teduglutide |
| Difference in clearance between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | To investigate the difference in clearance between SBS patients with and without teduglutide |
| Difference in half-life between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | To investigate the difference in half-life between SBS patients with and without teduglutide |
| Difference in Cmin between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | To investigate the difference in Cmin between SBS patients with and without teduglutide |
Countries
Belgium
Contacts
Primary ContactBarbara Deleenheer, PharmD
Outcome results
None listed