Effect of Food on Balcinrenone/Dapagliflozin Pharmacokinetics and the Pharmacokinetics of Balcinrenone When Dosed with a P‐gp Inhibitor

Abstract

Balcinrenone (AZD9977) is a novel selective non‐steroidal mineralocorticoid receptor antagonist with a distinct mode of action being developed as a fixed‐dose combination with the sodium–glucose cotransporter‐2 inhibitor dapagliflozin for the treatment of heart failure with impaired kidney function, and chronic kidney disease. In this Phase 1 randomized open‐label three‐way crossover study we investigated the effect of food on balcinrenone/dapagliflozin pharmacokinetics, and the pharmacokinetics of balcinrenone when dosed with a P‐glycoprotein (P‐gp) inhibitor. Fourteen healthy participants were administered an oral capsule of balcinrenone/dapagliflozin 40 mg/10 mg in three dosing periods: fasted (reference), fed (high‐fat, high‐calorie meal) and with a P‐gp inhibitor (quinidine 300 mg × 2). Balcinrenone exposure was comparable in the fed and fasted states (geometric mean ratios [GMRs] [90% CI]: maximum plasma concentration [Cmax] 1.05 [0.88, 1.25]; area under the plasma concentration–time curve from time 0 to infinity [AUCinf] 1.12 [1.06, 1.19]). In the fed state, dapagliflozin AUCinf was comparable to the fasted state (GMR [90% CI] 1.05 [1.01, 1.09]), whereas Cmax was decreased (GMR [90% CI] 0.59 [0.51, 0.69]), in line with previous dapagliflozin food interaction studies. Co‐administration with quinidine increased balcinrenone exposure: GMRs (90% CI) 1.48 (1.24, 1.76) and 1.24 (1.17, 1.31) for Cmax and AUCinf, respectively, but AUC fold increase was <2, the level used for classification of sensitive P‐gp substrates. All interventions were well tolerated. In conclusion, this study supports dosing of balcinrenone/dapagliflozin without regard to food. Balcinrenone is not considered a sensitive P‐gp substrate. No P‐gp based dosing precautions are warranted based on this study.