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

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).

Study Overview

• Status: Recruiting
• Conditions: Anticoagulation; Short Bowel Syndrome
• Intervention / Treatment: Drug: Apixaban single dose; Drug: Apixaban steady-state

• Study Type: Interventional
• Enrollment (Estimated): 84
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Barbara Deleenheer, PharmD; Phone Number: 003216342504; Email: barbara.deleenheer@uzleuven.be

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Recruiting
    • University Hospitals Leuven
    • Contact: Barbara Deleenheer, PharmD; Email: barbara.deleenheer@uzleuven.be
    • Contact: Deleenheer

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven

Publications and helpful links

General Publications

• Jeppesen PB. Spectrum of short bowel syndrome in adults: intestinal insufficiency to intestinal failure. JPEN J Parenter Enteral Nutr. 2014 May;38(1 Suppl):8S-13S. doi: 10.1177/0148607114520994. Epub 2014 Jan 31.
• Santamaria MM, Villafranca JJA, Abiles J, Lopez AF, Rodas LV, Goitia BT, Navarro PU. Systematic review of drug bioavailability following gastrointestinal surgery. Eur J Clin Pharmacol. 2018 Dec;74(12):1531-1545. doi: 10.1007/s00228-018-2539-9. Epub 2018 Aug 22.
• Eikelboom JW, Quinlan DJ, Hirsh J, Connolly SJ, Weitz JI. Laboratory Monitoring of Non-Vitamin K Antagonist Oral Anticoagulant Use in Patients With Atrial Fibrillation: A Review. JAMA Cardiol. 2017 May 1;2(5):566-574. doi: 10.1001/jamacardio.2017.0364.

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2020
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: April 3, 2020
• First Submitted That Met QC Criteria: April 9, 2020
• First Posted (Actual): April 14, 2020

Study Record Updates

• Last Update Posted (Estimated): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Apixaban
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Postoperative Complications; Disease; Gastrointestinal Diseases; Intestinal Diseases; Malabsorption Syndromes; Syndrome; Short Bowel Syndrome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban
• Other Study ID Numbers: s63950

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will be coded according to General Data Protection Regulation

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No