Pharmacokinetics and Dialyzability of Dapagliflozin in Dialysis Patients (DARE-ESKD 1)

Pharmacokinetics and Dialyzability of Dapagliflozin in Dialysis Patients: on Behalf of the DARE-ESKD Trial

Sodium-glucose co-transporter 2 inhibitors (Sglt2i) attenuate the incidence of cardiovascular events in individuals with preserved or mildly reduced kidney function. Whether this benefit is also observed among individuals with end-stage renal disease (ESRD), in whom cardiovascular disease is a leading cause of mortality, remains unexplored. To appraise the influence of dialysis on the pharmacokinetics of Sglt2i is a prerequisite to determining the treatment regimen that best fits this population.

In this study ESRD individuals, aged 18 years and older, on a regular dialysis regimen for a minimum of 3 months at the Nephrology Division of the Clinics Hospital of the University of Campinas (Unicamp) will be enrolled in a pharmacokinetics study.

In the single-dose protocol, hemodialysis participants will take Dapagliflozin 10mg P.O. immediately before the dialysis session, and blood samples will be collected every 30min during dialysis and again 24h and 48h after termination. The dialysate will be continuously sampled in a tank and aliquots collected for further analysis.

In the multiple-dose protocol, both hemodialysis and peritoneal dialysis participants will take Dapagliflozin 10mg P.O. daily in the morning for 7 days. Blood samples will be collected at baseline, and again after 48h and 7 days.

The plasma levels of dapagliflozin and its inactive metabolite, D3OG, will be calculated from blood and dialysate samples using liquid chromatography mass spectrometry.

The primary outcome is the plasma concentration-time curve of dapagliflozin and its inactive metabolite D3OG during a regular hemodialysis session. Secondary outcomes are: (i) the steady-state plasma concentration of Dapa; (ii) the accumulation ratio of Dapa; (iii) the total mass of Dapa and D3OG extracted by the dialysate; (iv) the dialytic clearance of dapagliflozin.

Study Overview

• Status: Completed
• Conditions: End-stage Renal Disease
• Intervention / Treatment: Drug: Dapagliflozin 10Mg Tab

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • SP
    • Campinas, SP, Brazil, 13083-887
      • University of Campinas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Dialysis for 3 months or more prior to enrollment
• 18 years of age or older
• Signed the informed consent form

Exclusion Criteria:

• Liver dysfunction
• Allergy to dapagliflozin
• Currently receiving a Sglt2i

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin; Dapagliflozin 10mg P.O.	Drug: Dapagliflozin 10Mg Tab; Participants will take a single-dose Dapagliflozin 10mg P.O. prior to the hemodialysis session for the single-dose pharmacokinetics protocol. In the multiple-dose protocol, Dapagliflozin 10mg P.O. will be taken daily in the morning for one week.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the curve of the plasma concentration-time curve of dapagliflozin	AUC of dapagliflozin (ng.mL / mL)	From dialysis initiation to 48 hours post- drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the curve of the plasma concentration-time curve of D3OG	AUC of D3OG (ng.mL / mL)	From dialysis initiation to 48 hours post- drug administration
Steady-state plasma concentration of Dapagliflozin	Steady-state plasma concentration (ng/mL)	7 days
Steady-state accumulation ratio of Dapagliflozin	Accumulation index	7 days
Total mass of dapagliflozin extracted by the dialysis	Dapagliflozin mass (mg)	7 days

Collaborators and Investigators

• Sponsor: University of Campinas, Brazil

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2022
• Primary Completion (Actual): September 1, 2022
• Study Completion (Actual): October 1, 2022

Study Registration Dates

• First Submitted: April 7, 2022
• First Submitted That Met QC Criteria: April 22, 2022
• First Posted (Actual): April 25, 2022

Study Record Updates

• Last Update Posted (Estimate): March 9, 2023
• Last Update Submitted That Met QC Criteria: March 8, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: peritoneal dialysis; hemodialysis; dapagliflozin
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 50393421.4.0000.5404

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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