Dataset Information

Evaluation of the Pharmacokinetics and Exposure-Response Relationship of Dapagliflozin in Patients without Diabetes and with Chronic Kidney Disease.

ABSTRACT:

Background and objective

Dapagliflozin, a sodium-glucose co-transporter inhibitor, was originally developed as an oral glucose-lowering drug for the treatment of type 2 diabetes mellitus. Emerging data suggest that cardiovascular and kidney benefits extend to patients without diabetes. Limited pharmacological data are, however, available in patients without diabetes. We aimed to characterise the pharmacokinetic profile of dapagliflozin in patients with chronic kidney disease without type 2 diabetes.

Methods

Plasma samples were collected in a randomised, placebo-controlled, double-blind, cross-over trial (DIAMOND, NCT03190694, n = 53) that assessed the effects of 10 mg of dapagliflozin in patients with a glomerular filtration rate ≥ 25 mL/min/1.73 m² and proteinuria > 500 mg/day. Mixed-effects models were used to develop a pharmacokinetic model and to evaluate the association between plasma exposure and response.

Results

Plasma concentrations (n = 430 observations) from 48 patients (mean age 50.8 years, mean glomerular filtration rate 57.9 mL/min/1.73 m², median proteinuria 1115 mg/24 h) were best described using a two-compartment model with first-order elimination. Apparent clearance and volume of distribution were 11.7 (95% confidence interval 10.7-12.7) L/h and 44.9 (95% confidence interval 39.0-50.9) L, respectively. Median dapagliflozin plasma exposure was 740.9 ng h/mL (2.5th-97.5th percentiles: 434.0-1615.3). Plasma exposure increased with decreasing kidney function. Every 100-ng h/mL increment in dapagliflozin plasma exposure was associated with a decrease in the urinary albumin:creatinine ratio (β = - 2.8%, p = 0.01), glomerular filtration rate (β = - 0.5 mL/min/1.73 m², p < 0.01) and systolic blood pressure (β = - 0.4 mmHg, p = 0.03).

Conclusions

The dapagliflozin plasma concentration-time profile in patients with non-diabetic kidney disease appears similar to the profile of patients with diabetic kidney disease described in the literature. Furthermore, the plasma exposure was associated with changes in risk markers for kidney disease.

SUBMITTER: van der Aart-van der Beek AB

PROVIDER: S-EPMC8016788 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:IntroductionPatients with chronic kidney disease (CKD) and peripheral artery disease (PAD) are more likely to undergo lower extremity amputation than patients with preserved kidney function. We sought to determine whether patients with CKD were less likely to receive pre-amputation care in the 1-year prior to lower extremity amputation compared to patients without CKD.MethodsWe conducted a retrospective observational study of patients with PAD-related lower extremity amputation between January 2014 and December 2017 using a large commercial insurance database. The primary exposure was CKD identified using billing codes and laboratory values. The primary outcomes were receipt of pre-amputation care, defined as diagnostic evaluation (ankle-brachial index, duplex ultrasound, and computed tomographic angiography), specialty care (vascular surgery, cardiology, orthopedic surgery, and podiatry), and lower extremity revascularization in the 1-year prior to amputation. We conducted separate logistic regression models to estimate the adjusted odds ratio (aOR) and 95% confidence intervals (CIs) among patients with and without CKD. We assessed for effect modification by age, sex, Black race, and diabetes status.ResultsWe identified 8,554 patients with PAD-related amputation. In fully adjusted models, patients with CKD were more likely to receive diagnostic evaluation (aOR 1.30; 95% CI 1.17-1.44) and specialty care (aOR 1.45, 95% CI 1.27-1.64) in the 1-year prior to amputation. There was no difference in odds of revascularization by CKD status (aOR 1.03, 0.90-1.19). Age, sex, Black race, and diabetes status did not modify these associations.Discussion/conclusionPatients with CKD had higher odds of receiving diagnostic testing and specialty care and similar odds of lower extremity revascularization in the 1-year prior to amputation than patients without CKD. Disparities in access to pre-amputation care do not appear to explain the higher amputation rates seen among patients with CKD.

Project description:IntroductionDapagliflozin is an orally administered selective sodium-glucose cotransporter 2 (SGLT2) inhibitor under development for the treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin lowers blood glucose through a reduction in renal glucose reabsorption. This study was performed to assess the effect of the oral antidiabetic agent voglibose [0.2 mg thrice daily (t.i.d.)] at steady-state, on the pharmacokinetics, safety and tolerability of dapagliflozin administered as a single oral dose (10 mg) to Japanese patients with T2DM.MethodsThis was an open-label, multi-center, drug-drug interaction study. A single oral dose of dapagliflozin (10 mg) was administered to 22 Japanese patients with T2DM in the presence and absence of voglibose (0.2 mg t.i.d.). Serial blood samples were collected before and at regular prespecified intervals after each dapagliflozin dose to determine dapagliflozin plasma concentrations and to evaluate pharmacokinetic parameters. Based on a mixed effect analysis of variance model, including the dosing condition as a fixed effect and patients as a random effect, the ratios of geometric means of area under curve from time 0 to infinity (AUC0-inf) and maximum observed plasma concentration (C max) with and without voglibose were estimated along with two-sided 90% confidence intervals (CIs).ResultsIn Japanese patients with T2DM, the exposure to dapagliflozin following a single oral dose of dapagliflozin 10 mg was not influenced by the concomitant administration of voglibose (0.2 mg t.i.d.). The geometric ratio (90% CI) for dapagliflozin AUC0-inf with/without voglibose was 1.009 (0.954, 1.067), and for C max 1.040 (0.899, 1.204). The median time to C max (t max) and plasma clearance of dapagliflozin were also similar between treatments. The mean half-life (t ½) for dapagliflozin was slightly higher when administered in combination with voglibose. Dapagliflozin 10 mg was well tolerated when administered alone and in combination with voglibose in Japanese patients with T2DM.ConclusionThe results presented here support the co-administration of dapagliflozin and voglibose without dose adjustment of either agent.

Project description:BackgroundDietary intervention at the early stage of chronic kidney disease (CKD) is important for preventing progression to the end-stage renal disease (ESRD). However, few studies have investigated dietary intake of CKD patients in non-dialysis stage. Therefore, we investigated the dietary intake of Korean non-dialysis CKD patients and aimed to establish baseline data for the development of dietary education and intervention strategies for CKD patients.MethodsThree hundred fifty CKD patients who visited Seoul National University Hospital outpatient clinic from February 2016 to January 2017 were recruited for this cross-sectional study. Subjects on dialysis and those who had undergone kidney transplantation were excluded. Dietary intake, demographic information, and biochemical characteristics of 256 subjects who completed three-day dietary records were analyzed. Subjects were divided into four groups based on diabetes mellitus (DM) (DM-CKD and Non-DM-CKD groups) and kidney function (Early-CKD and Late-CKD groups).ResultsTotal energy intake was lower in the Late-CKD group compared with the Early-CKD group. In men, carbohydrate intake was higher and protein and fat intakes tended to be lower in the Late-CKD group compared with the Early-CKD group. In women, carbohydrate intake tended to be lower in the DM-CKD group than the Non-DM-CKD group. Protein intake tended to be higher in the DM-CKD groups. Phosphorus and sodium intakes were higher in the DM-CKD groups compared with the Non-DM-CKD groups in women, and tended to be higher in the DM-CKD groups in men.ConclusionDM and kidney function affected energy and nutrient intakes. Subjects in the Late-CKD group consumed less energy than those in the Early-CKD group. Non-DM subjects seemed to restrict protein intake starting from the Early-CKD stage than subjects with DM. Subjects in this study had low energy and high sodium intakes compared with recommended levels. Protein intake was lower in advanced CKD patients, but their intake level was still higher than the recommendation. Dietary intervention strategies for non-dialysis CKD patients need to be customized depending on the presence of DM and kidney function.