Concentration–QT modeling demonstrates that the selective mineralocorticoid receptor modulator, balcinrenone (AZD9977), does not prolong QT interval
(2024) In CPT: Pharmacometrics and Systems Pharmacology- Abstract
Balcinrenone (AZD9977) is a selective mineralocorticoid receptor modulator in development in combination with dapagliflozin for treatment of heart failure with impaired kidney function and chronic kidney disease. A prespecified concentration–QT analysis was performed based on data from a phase I single ascending dose study prospectively designed as a thorough QT study substitute. Oral single doses of balcinrenone of 5–800 mg, plus fractionated doses of 800 and 1200 mg, were evaluated in 62 healthy male participants. Time-matched 12-lead digital electrocardiogram and plasma concentrations were measured pre-dose and up to 48 h postdose in the participants. Analysis was performed using a linear mixed-effect model, where baseline-adjusted... (More)
Balcinrenone (AZD9977) is a selective mineralocorticoid receptor modulator in development in combination with dapagliflozin for treatment of heart failure with impaired kidney function and chronic kidney disease. A prespecified concentration–QT analysis was performed based on data from a phase I single ascending dose study prospectively designed as a thorough QT study substitute. Oral single doses of balcinrenone of 5–800 mg, plus fractionated doses of 800 and 1200 mg, were evaluated in 62 healthy male participants. Time-matched 12-lead digital electrocardiogram and plasma concentrations were measured pre-dose and up to 48 h postdose in the participants. Analysis was performed using a linear mixed-effect model, where baseline-adjusted Fridericia-corrected QT interval (ΔQTcF) was a dependent variable and time-matched balcinrenone concentration an independent variable. The model fit was deemed adequate by evaluation of goodness-of-fit plots, and the slope of the concentration–ΔQTcF relationship was nonsignificant (−0.003 ms/μmol/L; 95% confidence interval [CI]: −0.181, 0.176). The high clinical exposure scenario was defined as the maximum concentration (2.156 μmol/L) following the highest expected therapeutic dose (40 mg once daily) under fed conditions and in presence of a strong cytochrome P450 3A4 inhibitor. Estimated baseline-adjusted and placebo-corrected QTcF interval (ΔΔQTcF) at this concentration was 0.35 ms (90% CI: −1.29, 2.00). Furthermore, the upper 90% ΔΔQTcF CI was estimated to be below the threshold of regulatory concern of 10 ms at all observed concentrations (up to 16.7 μmol/L). Hence, it can be concluded that balcinrenone does not induce QTcF prolongation at the high clinical exposure scenario.
(Less)
- author
- Sundell, Jesper LU ; Rekic, Dinko ; Melin, Johanna ; Johansson, Susanne ; Ebrahimi, Ahmad ; Dota, Corina and Parkinson, Joanna
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- epub
- subject
- in
- CPT: Pharmacometrics and Systems Pharmacology
- publisher
- American Society for Clinical Pharmacology and Therapeutics
- external identifiers
-
- scopus:85208261242
- pmid:39497618
- DOI
- 10.1002/psp4.13272
- language
- English
- LU publication?
- yes
- id
- 0a58518a-1c3d-46a7-b343-ffa44cc3dea8
- date added to LUP
- 2024-12-18 11:02:35
- date last changed
- 2025-07-17 04:04:00
@article{0a58518a-1c3d-46a7-b343-ffa44cc3dea8,
abstract = {{<p>Balcinrenone (AZD9977) is a selective mineralocorticoid receptor modulator in development in combination with dapagliflozin for treatment of heart failure with impaired kidney function and chronic kidney disease. A prespecified concentration–QT analysis was performed based on data from a phase I single ascending dose study prospectively designed as a thorough QT study substitute. Oral single doses of balcinrenone of 5–800 mg, plus fractionated doses of 800 and 1200 mg, were evaluated in 62 healthy male participants. Time-matched 12-lead digital electrocardiogram and plasma concentrations were measured pre-dose and up to 48 h postdose in the participants. Analysis was performed using a linear mixed-effect model, where baseline-adjusted Fridericia-corrected QT interval (ΔQTcF) was a dependent variable and time-matched balcinrenone concentration an independent variable. The model fit was deemed adequate by evaluation of goodness-of-fit plots, and the slope of the concentration–ΔQTcF relationship was nonsignificant (−0.003 ms/μmol/L; 95% confidence interval [CI]: −0.181, 0.176). The high clinical exposure scenario was defined as the maximum concentration (2.156 μmol/L) following the highest expected therapeutic dose (40 mg once daily) under fed conditions and in presence of a strong cytochrome P450 3A4 inhibitor. Estimated baseline-adjusted and placebo-corrected QTcF interval (ΔΔQTcF) at this concentration was 0.35 ms (90% CI: −1.29, 2.00). Furthermore, the upper 90% ΔΔQTcF CI was estimated to be below the threshold of regulatory concern of 10 ms at all observed concentrations (up to 16.7 μmol/L). Hence, it can be concluded that balcinrenone does not induce QTcF prolongation at the high clinical exposure scenario.</p>}},
author = {{Sundell, Jesper and Rekic, Dinko and Melin, Johanna and Johansson, Susanne and Ebrahimi, Ahmad and Dota, Corina and Parkinson, Joanna}},
language = {{eng}},
publisher = {{American Society for Clinical Pharmacology and Therapeutics}},
series = {{CPT: Pharmacometrics and Systems Pharmacology}},
title = {{Concentration–QT modeling demonstrates that the selective mineralocorticoid receptor modulator, balcinrenone (AZD9977), does not prolong QT interval}},
url = {{http://dx.doi.org/10.1002/psp4.13272}},
doi = {{10.1002/psp4.13272}},
year = {{2024}},
}