Background and Purpose: Selective endothelin A (ETA) antagonism has shown promise as a potential treatment for chronic kidney disease (CKD), but the adverse effect of fluid retention associated with ETA antagonists has limited their clinical utility. Combination of low doses of the selective ETA antagonist zibotentan with a fixed-dose sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin is currently being evaluated in the Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD) clinical trial as an approach to maximize kidney protection via ETA antagonism and SGLT2 inhibition in combination. Approach: This study utilized a quantitative systems pharmacology modeling approach to simulate the dose-response relationship of zibotentan alone and in combination with dapagliflozin in a virtual CKD patient population. Key Results: Simulations predict that interstitial fluid volume (IFV) changes will remain below baseline for zibotentan doses below 0.5 mg when combined with dapagliflozin, while the combination therapy will provide substantial additional improvements in urinary albumin-to-creatinine ratio (uACR), glomerular hypertension, and proximal tubule energy demand, indicating enhanced renoprotection. The simulation also indicate that patients with higher baseline eGFR (>30 mL/min/1.73m2) and baseline uACR (>800 mg/g) may experience greater kidney protective response to the combination therapy with less potential for detrimental fluid retention. Conclusions and impact: If the predicted results are confirmed by the ZENITH-CKD trial, this analysis will enhance mechanistic understanding of the balance between albuminuria reduction and fluid retention with this combination treatment strategy, and will provide a tool to inform optimal population selection for late phase clinical studies and lifecycle management planning.

Background and Purpose: Endothelin-1 (ET1) receptor A (ETA) antagonists reduce proteinuria and prevent renal outcomes in patients with chronic kidney disease (CKD), but their utility has been limited because of associated fluid retention and increased heart failure risk in patients with left ventricular dysfunction. Understanding mechanisms of fluid retention could result in solutions that preserve their renoprotective effects while mitigating fluid retention, but the complexity of the endothelin system has made identification of the underlying mechanisms challenging. Approach: We utilized a previously developed mathematical model of ET-1 kinetics, ETA antagonism, kidney function, and sodium and water homeostasis to evaluate mechanistic hypotheses of fluid retention with ETA antagonism. To do this, we simulated the RADAR clinical trial of atrasentan in patients with type 2 diabetes and CKD, and evaluated the model’s ability to predict observed decreases in hematocrit, urine albumin creatinine ratio (UACR), mean arterial pressure (MAP) and estimated glomerular filtration rate (eGFR). Key Results: An effect of ETA antagonism on venodilation and increased venous capacitance was found to be the critical mechanism necessary to reproduce the simultaneous decrease in both MAP and hematocrit observed in RADAR. Conclusions and impact: These findings indicate that fluid retention with ETA antagonism may not be caused by a direct anti-diuresis effect within the kidney, but may instead be an adaptive response to venodilation and increased venous capacity, which acutely tends to reduce cardiac filling pressure and cardiac output, and that fluid retention occurs in an attempt to maintain cardiac filling and cardiac output.

Aim: Dapagliflozin improves glycaemic control in patients with type 2 diabetes mellitus (T2DM) and is approved in European and Japanese patients with type 1 diabetes mellitus (T1DM) with inadequate glycaemic control. The objectives of this work were to characterise the dapagliflozin pharmacokinetics (PK) in patients with T1DM, assess the influence of covariates on dapagliflozin PK, and compare dapagliflozin systemic exposure between patients with T1DM and T2DM. Methods: Population PK analysis was performed using a non-linear mixed-effect modelling approach. The analysis included 5,793 dapagliflozin plasma concentrations from 1,150 adult patients with T1DM, collected from one phase 2 (NCT01498185) and two phase 3 studies (DEPICT-1, NCT02268214; DEPICT-2, NCT02460978). Covariate effects were investigated using stepwise covariate modelling. Model-derived area under the concentration-time curve (AUC) was compared with AUC in patients with T2DM. Results: The final two-compartmental model adequately described the dapagliflozin concentrations in patients with T1DM. The estimated apparent clearance was 20.5 L/h. Model-predicted systemic exposure for 5 mg and 10 mg of dapagliflozin indicated dose-proportionality and was comparable between patients with T1DM and T2DM. The identified covariate relationships showed that patients with better renal function (measured as estimated glomerular filtration rate), males, and heavier patients had lower dapagliflozin systemic exposure. Among the covariates studied, no covariates affected dapagliflozin systemic exposure to a clinically relevant extent. Conclusions: Dapagliflozin PK in patients with T1DM was adequately described by the population PK model and no clinically relevant covariates were identified. Dapagliflozin systemic exposure was comparable between patients with T1DM and T2DM. NCT01498185, NCT02268214, NCT02460978