Dados do Trabalho

Título

PHARMACOKINETIC PROPERTIES OF DAPAGLIFLOZIN IN HEMODIALYSIS AND PERITONEAL DIALYSIS PATIENTS

Introdução

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) attenuate cardiovascular events in individuals with conservatively managed chronic kidney disease, regardless of baseline glomerular filtration rate. As this condition progresses to kidney failure, withdrawal of these drugs is recommended as the influence of dialysis on the safety and pharmacokinetics (Pk) of dapagliflozin is unknown. As a result, this population, that is at a very-high cardiovascular risk, are restrained from SGLT2i benefits.

Material e Método

This prospective, single-center, open-label trial aimed to assess the Pk and safety of dapagliflozin in individuals on dialysis compared to age- and gender-matched controls. Secondary goal was to determine the dialyzability of dapagliflozin and of its inactive metabolite, D3OG. Blood and dialysate samples were collected during dialysis every 30min for 4h, and again 48h after a single-dose of dapagliflozin, and this protocol was repeated after 6 daily doses for steady-state concentration and accumulation ratio assessments. Liquid chromatography assays measured samples` levels of dapagliflozin and D3OG, and Pk parameters were derived from the area under the plasma concentration – time curves (AUC). The total mass of drug removed was based on the relative difference between plasma and dialysate AUC, and both adverse events and biochemical markers were disclosed for safety reporting.

Resultados

The dialysis group consisted of 7 participants, with a median dialysis duration of 4.7 years. The peak concentration (Cmax) of dapagliflozin was 117ng/mL and 98ng/mL in the dialysis and control groups, respectively, with accumulation ratios of 26.7% and 9.5%. Both groups had similar dapagliflozin time to Cmax (tmax) of 1h and half-life time (t1/2) of 7h. The Cmax of D3OG was 237ng/mL in the dialysis group and 201ng/mL in controls, and the respective Tmax and t1/2 were 1.5h and 17h, respectively. Dapagliflozin recovered from dialysate accounted for <0.10% of the administered dose. No serious adverse events were reported in neither group, nor were there any significant post-treatment biochemical changes.

Discussão e Conclusões

This study demonstrated for the first time that dapagliflozin is a reliable therapeutic target for individuals on dialysis. By providing robust evidence that neither safety nor Pk were appreciably affected by dialysis, the present results set the ground for future investigations aimed to evaluate the extension of the SGLT2i benefits also to patients with kidney failure.

Palavras Chave

Dapagliflozin; SGLT2i; dialysis; renal replacement therapy; pharmacokinetics.