Aims: The aim of this phase 1 trial was to assess the pharmacokinetics, safety, and tolerability of balcinrenone (previously AZD9977) in participants with severe renal impairment versus those with normal renal function. Methods: Participants with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) not on dialysis were compared with group-matched control participants with eGFR ≥90 mL/min/1.73 m2. Eligible participants received a single oral dose of 150 mg balcinrenone, and blood and urine samples were collected for analysis. Results: The total apparent balcinrenone clearance was 50% lower in the severe renal impairment group, resulting in a ~two-fold higher area under the curve (AUC) and a 1.4-fold higher maximum observed plasma concentration in the severe renal impairment group versus the control group. The terminal half-life and plasma protein binding were similar in both groups. Balcinrenone was safe and well tolerated in all participants. All adverse events reported were of mild-to-moderate severity and not considered related to balcinrenone. Conclusions: Balcinrenone exposure was approximately two-fold higher in participants with severe renal impairment compared with the group-matched control participants. Based on obtained results, the AUC exposure is predicted to be <50% higher in patients with an eGFR of 20 mL/min/1.73 m2 compared with those with an eGFR of 60 mL/min/1.73 m2. In light of these findings, no dose adjustment based on eGFR is needed in two ongoing studies that target these patients (MIRO-CKD [NCT06350123] and BalanceD-HF [NCT06307652]).

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