Pharmacokinetics of Apixaban in Patients With Short Bowel Syndrome Requiring Long Term Parenteral Nutrition

Study Overview
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Brief Summary
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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).

Official Title
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Pharmacokinetics of Apixaban in Patients With Short Bowel Syndrome Requiring Long Term Parenteral Nutrition

Conditions
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Short Bowel Syndrome, Anticoagulation

Intervention / Treatment
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* Drug: Apixaban single dose
* Drug: Apixaban steady-state


Participation Criteria
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Eligibility Criteria
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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 anticoagulation 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 anticoagulation 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 other anticoagulant agents 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 Exclusion criteria non-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 other anticoagulant agents concomitant intake of strong combined inhibitors of CYP3A4 and P-gp use of prokinetics, antimotility drugs or opioids participation in a recent (<1 month) trial with an investigational product

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Interventional, non-randomized, open label, monocentric controlled study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anticoagulation and teduglutide naive short bowel syndrome<br>Anticoagulation and teduglutide naive patients with short bowel syndrome requiring long term parenteral support | Drug: Apixaban single dose<br>* 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<br>* Other names: Eliquis single dose;|
| Experimental: Healthy volunteers<br>Anticoagulation naive healty volunteers | Drug: Apixaban single dose<br>* 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<br>* Other names: Eliquis single dose;|
| Other: Short bowel syndrome on apixaban<br>Patients with short bowel syndrome requiring long term parenteral support and taking apixaban 2.5 mg twice daily or 5 mg twice daily | Drug: Apixaban steady-state<br>* Steady-state apixaban PK characteristics will be measured in patients already treated with apixaban<br>* Other names: Eliquis steady-state;|
| Other: Patients with a normal gastrointestinal tract on apixaban<br>Patients with a normal gastrointestinal tract taking apixaban 2.5 mg twice daily or 5 mg twice daily | Drug: Apixaban steady-state<br>* Steady-state apixaban PK characteristics will be measured in patients already treated with apixaban<br>* Other names: Eliquis steady-state;|
| Experimental: Anticoagulation naive short bowel syndrome on teduglutide<br>Anticoagulation naive patients with short bowel syndrome requiring long term parenteral support and initiated on teduglutide | Drug: Apixaban single dose<br>* 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<br>* Other names: Eliquis single dose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Cmax of apixaban between SBS and patients with a normal gastrointestinal tract | 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 | Through study completion, an average of 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in estimated trough level (Cmin) of apixaban between SBS and patients with a normal gastrointestinal tract | 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 | Through study completion, an average of 1.5 years | 
| Difference in time to reach Cmax (Tmax) of apixaban between SBS patients and patients with a normal gastrointestinal tract | 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 | Through study completion, an average of 1.5 years | 
| Difference in exposure (AUC0-12h) of apixaban between SBS patients and patients with a normal gastrointestinal tract | 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 | Through study completion, an average of 1.5 years | 
| Difference in absorption rate constant of apixaban between SBS patients and patients with a normal gastrointestinal tract | To investigate the difference in absorption rate constant between patients with and without SBS requiring long-term PN | Through study completion, an average of 1.5 years | 
| Difference in bioavailability of apixaban between SBS patients and patients with a normal gastrointestinal tract | To investigate the difference in bioavailability between patients with and without SBS requiring long-term PN | Through study completion, an average of 1.5 years | 
| Difference in volume of distribution of apixaban between SBS patients and patients with a normal gastrointestinal tract | To investigate the difference in volume of distribution between patients with and without SBS requiring long-term PN | Through study completion, an average of 1.5 years | 
| Difference in clearance of apixaban between SBS patients and patients with a normal gastrointestinal tract | To investigate the difference in clearance between patients with and without SBS requiring long-term PN | Through study completion, an average of 1.5 years | 
| Difference in half-life of apixaban between SBS patients and patients with a normal gastrointestinal tract | To investigate the difference in half-life between patients with and without SBS requiring long-term PN | Through study completion, an average of 1.5 years | 
| To set up an optimized dosing scheme of apixaban for SBS patients | 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. | Through study completion, an average of 1.5 years | 
| Difference in Cmax between SBS patients with and without teduglutide | To investigate the difference in Cmax between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | 
| Difference in Cmin between SBS patients with and without teduglutide | To investigate the difference in Cmin between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | 
| Difference in Tmax between SBS patients with and without teduglutide | To investigate the difference in Tmax between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | 
| Difference in AUC SBS patients with and without teduglutide | 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 | Through study completion, an average of 1.5 years | 
| Difference in AUC between SBS patients with and without teduglutide | 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 | Through study completion, an average of 1.5 years | 
| Difference in absorption rate constant between SBS patients with and without teduglutide | To investigate the difference in absorption rate constant between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | 
| Difference in bioavailability between SBS patients with and without teduglutide | To investigate the difference in bioavailability between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | 
| Difference in volume of distribution between SBS patients with and without teduglutide | To investigate the difference in volume of distribution between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | 
| Difference in clearance between SBS patients with and without teduglutide | To investigate the difference in clearance between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | 
| Difference in half-life between SBS patients with and without teduglutide | To investigate the difference in half-life between SBS patients with and without teduglutide | Through study completion, an average of 1.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Apixaban, Pharmacokinetics