Pharmacokinetics and Dialyzability of Dapagliflozin in Dialysis Patients

Study Overview
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Brief Summary
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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.

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

Conditions
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End-stage Renal Disease

Intervention / Treatment
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* Drug: Dapagliflozin 10Mg Tab


Participation Criteria
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Eligibility Criteria
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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

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: In the single-dose protocol, hemodialysis participants will take the experimental drug immediately prior to the dialysis session. In the multiple-dose protocol, volunteers will take the drug daily in the morning for one week.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>Dapagliflozin 10mg P.O. | Drug: Dapagliflozin 10Mg Tab<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemodialysis, dapagliflozin, peritoneal dialysis