Abstract
Aim
Balcinrenone (previously AZD9977) is a novel selective non‐steroidal mineralocorticoid receptor antagonist (MRA) with a differential mechanism of action relative to approved MRAs. The aim of this trial was to assess the pharmacokinetics, safety and tolerability of balcinrenone in participants with mild and moderate hepatic impairment versus participants with normal hepatic function.
Methods
Participants with mild and moderate hepatic impairment (Child–Pugh Class A [n = 8] and Child–Pugh Class B [n = 8]) were compared with group matched controls with normal hepatic function [n = 9]. Eligible participants received a single oral dose of 50‐mg balcinrenone. Blood and urine samples were collected. Safety and tolerability were monitored.
Results
In participants with mild hepatic impairment, balcinrenone exposure (area under the plasma concentration–time curve [AUC] and maximum plasma concentration [C max]) was similar compared with participants with normal hepatic function. In participants with moderate hepatic impairment, C max was similar, but there was a slight and statistically significant 30% (90% CI 4%–61%) increase in AUC compared with participants with normal hepatic function. Balcinrenone was well tolerated. All reported adverse events were of mild to moderate intensity.
Conclusions
Compared with participants with normal hepatic function, balcinrenone exposure was similar in participants with mild hepatic impairment. AUC, but not C max, was slightly increased in participants with moderate hepatic impairment. We do not consider the minor AUC increase seen in participants with moderate hepatic impairment to be clinically relevant. Thus, we would not recommend any dose adjustment for patients with mild or moderate hepatic impairment.
Keywords: drug safety, heart failure, hepatic impairment, pharmacokinetics, Phase 1
What is already known about this subject
Balcinrenone is a nonsteroidal selective mineralocorticoid receptor antagonist under development in combination with the sodium–glucose cotransporter‐2 inhibitor dapagliflozin for the treatment of heart failure with impaired kidney function and for chronic kidney disease.
Metabolism is the major elimination route of balcinrenone. The intended target population of balcinrenone in combination with dapagliflozin may also have hepatic impairment.
What this study adds
This study investigated the pharmacokinetics, safety and tolerability of a single oral dose of 50‐mg balcinrenone in participants with mild (Child–Pugh Class A) and moderate (Child–Pugh Class B) hepatic impairment, compared with group‐matched controls with normal hepatic function.
Balcinrenone exposure was similar in participants with mild hepatic impairment and normal hepatic function. In participants with moderate hepatic impairment, there was a 30% increase in AUC compared with participants with normal hepatic function.
We did not consider the minor AUC increase in participants with moderate hepatic impairment to be clinically relevant. Thus, we would not recommend any dose adjustment for patients with mild or moderate hepatic impairment.
1. INTRODUCTION
Chronic heart failure (HF) is a progressive syndrome associated with substantial morbidity and mortality, and a significant burden on global healthcare systems. An estimated 64 million people were living with HF worldwide between 2017 and 2020. 1 In addition, many patients with HF also have chronic kidney disease (CKD) 2 , which complicates HF treatment and has a negative impact on prognosis. 3
Mineralocorticoid receptor antagonists (MRAs) are an important standard‐of‐care therapy for HF with left ventricular ejection fraction (LVEF) ≤40% and are part of the therapeutic options for patients with higher LVEF. 4 , 5 MRAs are, however, underused in HF, especially in patients with impaired renal function due to safety concerns of hyperkalaemia and an initial reduction in eGFR. 6 , 7
Balcinrenone (previously AZD9977) is a novel selective non‐steroidal MRA with a differential mode of action under development as a fixed‐dose combination with the sodium–glucose cotransporter‐2 inhibitor (SGLT2i) dapagliflozin for the treatment of patients with HF and impaired kidney function, and CKD. Nonclinical data have demonstrated that balcinrenone reduces albuminuria and improves cardiac and kidney pathology with similar efficacy to approved MRAs, without triggering the increase in urinary Na+/K+ ratio seen with typical MRAs. 8 This suggests a mechanism‐based differentiation for K+ retention versus approved MRAs and a reduced risk of causing hyperkalaemia. The efficacy and safety of balcinrenone in combination with dapagliflozin was investigated in patients with HF and CKD in the Phase 2b MIRACLE trial, 9 and is currently being evaluated in a Phase 3 study in patients with HF with impaired kidney function (BalanceD‐HF; ClinicalTrials.gov: NCT06307652). Recently, a dose‐finding study in patients with CKD was also completed (MIRO‐CKD; ClinicalTrials.gov: NCT06350123 10 ).
In Phase 1 studies, balcinrenone was administered in suspension to healthy male participants in single doses up to 1200 mg and in multiple ascending doses up to 300 mg twice daily. 11 , 12 In the multiple ascending doses study, balcinrenone was rapidly absorbed and exposure (area under the curve [AUC] and maximum observed plasma concentration [C max]) increased in a dose‐proportional manner up to doses of 200 mg. At higher doses, the increase in exposure was less than dose‐proportional due to solubility‐limited absorption. Accumulation ratio for balcinrenone 50 mg was 1.2 from Days 1 to 8 following twice daily dosing. This minor accumulation at steady state was hypothesized to result from colonic absorption, potentially affecting AUC estimation. 11 A dose‐dependent increase in mean serum aldosterone levels confirmed target engagement. 11 In these studies, balcinrenone was well tolerated with no safety concerns. 11 , 12
Following oral administration of balcinrenone 100‐mg capsules in a mass balance study, the absolute bioavailability of balcinrenone was 52%, and the degree of protein binding was 81.5%. As determined after intravenous administration, the elimination half‐life was 4 h, and apparent volume of distribution (Vz/F) was 37.8 L/h. After oral administration of [14C]balcinrenone suspension, unchanged balcinrenone was detected in both urine and faeces, accounting for 28.2% of the administered dose in excreta. Thus, metabolism is the major elimination route of balcinrenone. In vitro studies have shown that balcinrenone metabolism is primarily mediated by CYP3A4. The exposure to circulating balcinrenone metabolites is low, and the contribution of metabolites to the pharmacodynamic response is deemed to be negligible. 13 Renal clearance also contributes to the elimination of balcinrenone, and the total apparent balcinrenone clearance is 50% lower; AUC is consequently twofold higher in participants with severe renal impairment than in controls with normal renal function. 14
Once approved, the fixed‐dose combination of balcinrenone/dapagliflozin is intended for a target population that may also have mild and moderate hepatic impairment. Patients with severe hepatic impairment are already treated with high doses of MRA. Given the large contribution of metabolism to the elimination of balcinrenone, it is important to characterize the pharmacokinetics of balcinrenone in a population with hepatic impairment. The pharmacokinetics of dapagliflozin have previously been evaluated in a population with hepatic impairment 15 , supporting dosing in patients with impaired hepatic function. 16 , 17 Results from the clinical balcinrenone programme suggest balcinrenone doses up to 50 mg have the desired benefit/risk profile. This study was designed to evaluate the pharmacokinetics, safety, and tolerability of a single oral dose of 50‐mg balcinrenone in participants with mild and moderate hepatic impairment as defined by the Child–Pugh (CP) classification.
2. MATERIALS AND METHODS
This was a single‐dose, open‐label, nonrandomized, parallel‐group study of the pharmacokinetics of balcinrenone in participants with mild and moderate hepatic impairment (CP Classes A and B) and group‐matched participants with normal hepatic function (Figure 1). The design followed guidance on the investigation of pharmacokinetics in patients with impaired hepatic function. 18 , 19
FIGURE 1.
Study design. BMI, body mass index.
2.1. Ethics
The trial was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, with the International Conference on Harmonization Good Clinical Practice, with all applicable regulatory requirements, and with the AstraZeneca policy on bioethics. The study recruited participants across three sites in the United States and was approved by the Salus Central Institutional Review Board, Austin, TX, USA (Protocol#: D6402C00013). The study was registered (ClinicalTrials.gov: NCT06388616). All participants provided written informed consent before enrolment.
2.2. Participants
Eligible participants were male or female aged 18–79 years, weighed ≥50 kg and had a body mass index (BMI) of 18–42 kg/m2. Females of childbearing potential were required to use an approved method of highly effective contraception and to have a negative pregnancy test at screening and check‐in to the clinical unit. Participants were to be in good general health, except for additional specific inclusion criteria related to participants with hepatic impairment, as determined by the investigator. All participants had to have an eGFR of ≥60 mL/min/1.73 m2 (2021 CKD‐EPI creatinine formula 20 ) at screening. Use of strong and moderate inhibitors and inducers of CYP3A4 was not allowed. Participants treated with an MRA had to refrain from this medication for 10 h prior to and 10 h after study intervention. For a full list of restricted medications, see Appendix 1.
Participants with hepatic impairment had to have a diagnosis of chronic (≥6 months) and stable hepatic impairment (mild [Class A] or moderate [Class B] by CP classification 21 ) with no significant change in hepatic status within 30 days prior to screening and be stable on a concomitant medication and/or treatment regimen for ≥2 weeks prior to a screening visit.
Compared with the two groups with hepatic impairment (mild and moderate, respectively), the mean age of the participants with normal hepatic function had to be ±10 years, and the mean BMI had to be ±20% kg/m2. If not matched by mean levels on the above criteria, an additional one to four controls were to be recruited to ascertain the criteria. At least two participants of each sex had to be recruited to each group. In a population pharmacokinetic analysis, sex was not identified as a covariate of balcinrenone exposure. 22
2.3. Procedures
Potential participants were screened up to 4 weeks prior to study intervention. Eligible participants were admitted to the study site on Day −1. On Day 1, balcinrenone was administered to each participant as a single oral dose of a 50‐mg capsule after an overnight fast. Blood samples were collected before dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48, 72 and 96 h after dosing. Plasma samples for protein binding assessment were taken at 2 and 8 h post‐dose. Urine samples were collected pre‐dose, 0–12 and 12–24 h after dosing. Participants were discharged from the study site on Day 5, after the final pharmacokinetic blood sample. A final safety follow‐up was performed by a telephone call on Day 10 (±3 days) (Figure 1).
2.4. Balcinrenone quantitation
Plasma and urine samples were stored at −80°C (−112°F) until analysis. Balcinrenone concentrations were determined using liquid chromatography–tandem mass spectrometry (LC–MS/MS) following protein precipitation for plasma and sample dilution for urine according to validated and published methods. 11 The lower limit of quantitation of balcinrenone was 2.0 nmol/L in plasma and 10 nmol/L in urine. Results from in‐study quality control (QC) samples and calibration standards indicated acceptable assay performance. Interrun accuracy and precision (%CV) from the in‐study QC samples were in the ranges of 97.7%–105.2% and 9.7%–3.8% for plasma and 95.9%–110.6% and 7.8%–2.0% for urine, respectively, at QC concentrations of 6, 70, 800, 1600 and 32 000 nmol/L in plasma and 30, 500 and 8000 and 25 000 nmol/L in urine. To support the accuracy and precision of measurements established with spiked in‐study QC samples, incurred sample reanalysis was also performed during the study. For plasma, 45 of 46 (97.8%) reanalysed study samples were within 20% of the mean of the two values, well within the acceptance criteria in the current regulatory guidance. All study samples were analysed within the following established stability periods: 1078 days in plasma and 363 days in urine.
2.4.1. Determination of plasma protein binding in human plasma
The extent of binding of balcinrenone to human plasma proteins was determined by equilibrium dialysis using the high‐throughput equilibrium dialysis (HTDialysis) device following incubation for 4 h at 37°C (98.6°F) and 5% CO2 using plasma samples from the clinical study taken post‐dose at 2 and 8 h following oral administration of balcinrenone to healthy participants with normal hepatic function and to those with hepatic impairment. Concentrations were determined using a qualified method as previously described. 14 All samples were analysed within the validated 83‐day period.
2.5. Pharmacokinetics
Balcinrenone plasma and urine pharmacokinetic parameters were estimated by non‐compartmental methods using Phoenix WinNonlin (Certara Inc., Princeton, NJ, USA). Parameters included C max, time to C max (t max), elimination half‐life associated with terminal slope of a semi‐logarithmic concentration–time curve (t ½ λz), AUC from time zero to infinity (AUC inf) and to last measurable concentration (AUC last) and Vz/F. Nonrenal clearance (CL NR) was the difference between total apparent clearance (CL/F) and renal clearance (CL R).
Pharmacokinetic parameters were analysed using anova model with the natural logarithm of AUC inf, AUC last, and C max as response variables, and group (mild hepatic impairment, moderate hepatic impairment and normal hepatic function) as a fixed effect. For each primary pharmacokinetic variable, least squares (LS) means (with two‐sided 95% confidence intervals [CIs]) for each group as well as LS mean differences (with two‐sided 90% CIs) for each of the hepatic impairment groups versus the group with normal hepatic function were estimated. The results were back‐transformed to the original scale and presented with geometric means and geometric mean ratios with corresponding CIs. Restricted maximum likelihood estimation method was used for the CI calculation.
In exploratory analyses, regression models with CL/F, the logarithm of AUC last, AUC inf and C max as the dependent variable and the CP score, total bilirubin, serum albumin and prothrombin time as the independent variables were performed. The intercept α and the slope β together with CIs (two‐sided 95%) were estimated and presented.
2.6. Safety
Safety evaluations included the incidence, intensity and severity of adverse events (AEs) and serious AEs, physical examinations, monitoring of vital signs, 12‐lead electrocardiography and laboratory tests (blood and urine). The investigator assessed the causal relationship between treatment and any AEs.
2.7. Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24. 23
3. RESULTS
3.1. Participants
Twenty‐five participants were enrolled in the study: eight in the mild hepatic impairment group, eight in the moderate hepatic impairment group and nine in the group‐matched control group (Figure 1). The characteristics of participants are presented in Table 1. Participants' mean age and BMI were 63.1 years and 30.0 kg/m2 in the mild hepatic impairment group, 59.6 years and 30.4 kg/m2 in the moderate hepatic impairment group and 60.1 years and 27.8 kg/m2 in the matched control group. Most participants were white (22 [88%]) and female (14 [56%]). At screening, all participants fulfilled the inclusion criterion of eGFR ≥60 mL/min/1.73 m2. One subject in the normal hepatic function group had an eGFR <60 mL/min/1.73 m2 at baseline.
TABLE 1.
Baseline characteristics.
| Mild hepatic impairment, n = 8 | Moderate hepatic impairment, n = 8 | Matched controls, n = 9 | |
|---|---|---|---|
| Age, years | |||
| Median (IQR) | 64.5 (62.5–67.5) | 59.0 (55.5–64.0) | 59.0 (58.0–61.0) |
| Range | 46–70 | 52–68 | 53–68 |
| Female sex, n (%) | 5 (62.5) | 4 (50.0) | 5 (55.6) |
| Race, n (%) | |||
| White | 7 (87.5) | 8 (100) | 7 (77.8) |
| Black | 0 | 0 | 2 (22.2) |
| Asian | 1 (12.5) | 0 | 0 |
| Body mass index, kg/m2 | |||
| Median (IQR) | 30.70 (26.85–33.20) | 29.75 (27.95–33.80) | 27.90 (25.10–28.90) |
| Range | 21.0–37.9 | 22.5–38.1 | 24.2–32.9 |
| Weight, kg | |||
| Median (IQR) | 90.0 (63.0–95.0) | 79.5 (73.0–93.5) | 79.0 (70.0–95.0) |
| Range | 58–100 | 59–139 | 61–99 |
| eGFR, mL/min/1.73 m2 | |||
| Mean (IQR) | 99.5 (88.5–101.0) | 97.5 (81.0–104.0) | 98.0 (87.0–99.0) |
| Range | 69–111 | 65–112 | 56–104 |
| CP score, median (range) | 5.5 (5–6) | 7.0 (7–8) | NA |
| Serum albumin, g/L | |||
| Median (IQR) | 41.5 (37.5–42.5) | 42.0 (40.0–43.0) | 42.0 (41.0–45.0) |
Abbreviations: eGFR, estimated glomerular filtration rate; IQR, interquartile range.
Median CP score was 5.5 in the mild hepatic impairment group and 7 in the moderate hepatic impairment group. The participants in the hepatic impairment groups had stable hepatic disease, and participants in the normal hepatic function group were appropriately matched to the participants with hepatic impairment based on the predefined criteria. There were no notable baseline or demographic characteristics beyond differences in hepatic function considered to have affected the outcome of the study.
All participants received one dose of balcinrenone 50 mg, completed the study and were included in all analyses.
3.2. Pharmacokinetics
The geometric mean balcinrenone plasma concentration–time profiles after oral administration of a 50‐mg capsule were similar in participants with mild or moderate hepatic impairment compared to the mean profile in participants with normal hepatic function. Balcinrenone was rapidly absorbed followed by an apparent biphasic decline in plasma drug concentrations (Figure 2).
FIGURE 2.
Total balcinrenone plasma concentration–time profile following an oral dose of 50‐mg balcinrenone. (A) Geometric mean (±geometric standard deviation) plasma concentration of balcinrenone over time for each hepatic function group on a linear scale. Vertical lines represent one geometric standard deviation above and below the geometric mean. (B) Geometric mean plasma concentration of balcinrenone over time for each hepatic function group on a semi‐logarithmic scale.
Exposure to balcinrenone as assessed by AUC was similar in participants with mild hepatic impairment compared to participants with normal hepatic function (geometric mean ratio [90% CI] AUC inf 1.09 [0.88, 1.35]). In participants with moderate hepatic impairment compared to participants with normal hepatic function, exposure was approximately 1.3‐fold higher (AUC inf geometric mean ratio [90% CI] 1.30 [1.04, 1.61]). C max, as well as t max, was similar in participants with moderate and mild hepatic impairment and in participants with normal hepatic function (Tables 2 and 3).
TABLE 2.
Statistical comparison of key balcinrenone plasma pharmacokinetic parameters following a 50‐mg dose.
| Comparison with normal hepatic function | ||||
|---|---|---|---|---|
| Hepatic function | n | Geometric mean (95% CI) | Geometric mean ratio (%) (90% CI) | |
| C max (nmol/L) | Normal | 9 | 1778 (1436, 2200) | |
| Mild hepatic impairment | 8 | 1718 (1370, 2154) | 0.97 (0.75, 1.25) | |
| Moderate hepatic impairment | 8 | 1684 (1343, 2112) | 0.95 (0.73, 1.23) | |
| AUC last (h*nmol/L) | Normal | 9 | 6402 (5343, 7671) | |
| Mild hepatic impairment | 8 | 6976 (5758, 8451) | 1.09 (0.88, 1.36) | |
| Moderate hepatic impairment | 8 | 8240 (6802, 9982) | 1.29 (1.03, 1.60) | |
| AUC inf (h*nmol/L) | Normal | 9 | 6423 (5366, 7689) | |
| Mild hepatic impairment | 8 | 7005 (5788, 8477) | 1.09 (0.88, 1.35) | |
| Moderate hepatic impairment | 8 | 8332 (6884, 10 080) | 1.30 (1.04, 1.61) |
Abbreviations: AUC, area under the plasma concentration–time curve; AUC inf, AUC from time zero to infinity; AUC last, AUC from time zero to time of last quantifiable concentration; CI, confidence interval; C max, maximum observed plasma concentration; h, hours.
TABLE 3.
Balcinrenone pharmacokinetic parameters following a 50‐mg oral dose.
| Mild hepatic impairment, n = 8 | Moderate hepatic impairment, n = 8 | Matched controls, n = 9 | |
|---|---|---|---|
| Geometric mean (gCV%) a | |||
| C max (nmol/L) | 1718 (35) | 1684 (24) | 1778 (35) |
| AUC last (h*nmol/L) | 6976 (25) | 8240 (19) | 6402 (33) |
| AUC inf (h*nmol/L) | 7005 (25) | 8332 (19) | 6423 (33) |
| t max (h) a | 1.75 (0.75–4.0) | 2.00 (1.50–4.00) | 1.50 (1.00–4.00) |
| t ½ λz (h) | 5.0 (58) | 9.8 (79) | 4.7 (50) |
| Vz/F (L/h) | 128 (59) | 212 (88) | 133 (64) |
| CL/F (L/h) | 17.9 (25) | 15.0 (19) | 19.5 (33) |
| CL NR (L/h) | 13.1 (41) | 11.7 (27) | 15.8 (43) |
| CL R (L/h) | 4.1 (48) | 3.1 (34) | 2.6 (170) |
| fu (%) | 20.9 (11) | 22.6 (13) | 22.2 (9) |
Abbreviations: AUC, area under the plasma concentration–time curve; AUC inf, AUC from time zero to infinity; AUC last, AUC from time zero to time of last quantifiable concentration; CL/F, total apparent clearance; CL NR, nonrenal clearance; CL R, renal clearance; C max, maximum observed plasma concentration; h, hours; fu, fraction unbound; t ½ λz, half‐life associated with terminal slope of a semi‐logarithmic concentration–time curve; t max, time to reach maximum observed plasma concentration; Vz/F, apparent volume of distribution during the terminal phase.
t max is given as median (range).
The geometric mean t 1/2 λz in participants with moderate hepatic impairment was longer (9.8 h) compared to participants with mild hepatic impairment (5.0 h) and participants with normal hepatic function (4.7 h). Geometric mean Vz/F was higher in participants with moderate hepatic impairment (212 L) compared to participants with mild hepatic impairment and participants with normal hepatic function (128 and 133 L, respectively). Geometric mean CL/F in participants with moderate and mild hepatic impairment and participants with normal hepatic function was 15.0, 17.9, and 19.5 L/h, respectively. Geometric mean CL NR was higher in participants with normal hepatic function (15.8 L/h) compared to participants with mild and moderate hepatic impairment (13.1 and 11.7 L/h, respectively; Table 2).
Geometric mean CL R in the mild and moderate hepatic impairment groups and normal hepatic function group was approximately 4.1, 3.1, and 2.6 L/h, respectively. The between‐participant variability (geometric CV%) for CL R was 48% and 34% in the mild and moderate hepatic impairment groups, but 170% in the normal hepatic function group. Of note, two participants with normal hepatic function had a urine volume of <1 L during the 24‐h collection.
In plasma samples obtained at 2 and 8 h postdose, the geometric mean unbound fraction of balcinrenone, fu (gCV%), was similar in participants with mild and moderate hepatic impairment and in participants with normal hepatic function; 20.9% (11) and 22.6% (13) and 22.2% (9), respectively (Table 3).
The results from the exploratory regression analyses of the relationship between balcinrenone pharmacokinetic parameters (C max, AUC inf, AUC last and CL/F) and measures of hepatic impairment (CP score, serum bilirubin, serum albumin, and prothrombin time) are presented in Figures S1–S4 in Supporting information. Visual inspection suggested associations between some parameters (i.e., CP score and prothrombin time, respectively, vs. CL/F), whereas for others, there appeared to be little relationship. Because the analyses were exploratory, no formal hypothesis testing was performed.
3.3. Safety
Treatment with a single oral dose of balcinrenone 50 mg was safe and well tolerated in participants with mild or moderate hepatic impairment as well as in participants with normal hepatic function. In total, two participants, one (12.5%) from the moderate hepatic impairment group and one (11.1%) from the normal hepatic function group, experienced a total of two non‐serious AEs after receiving intervention (Table 4): laryngeal pain and headache. The reported AEs were of mild to moderate intensity and reported as resolved before the end of the residential period. The AE of headache was considered related to balcinrenone by the investigator. There were no serious AEs or deaths. No clinically significant trends or shifts from baseline were reported for laboratory results, vital signs or electrocardiographic findings.
TABLE 4.
Adverse events following administration of a single oral dose of 50‐mg balcinrenone.
| Mild hepatic impairment, n = 8 | Moderate hepatic impairment, n = 8 | Matched controls, n = 9 | Overall, n = 25 | |
|---|---|---|---|---|
| Participants with any adverse events, n (%) | 0 (0) | 1 (12.5) | 1 (11.1) | 2 (8.0) |
| Serious adverse event, n (%) | 0 | 0 | 0 | 0 |
| Adverse event leading to withdrawal from study, n (%) | 0 | 0 | 0 | 0 |
| Nervous system disorders | 0 | 0 | 1 (11.1) | 1 (4.0) |
| Headache | 0 | 0 | 1 (11.1) | 1 (4.0) |
| Respiratory, thoracic and mediastinal disorders | 0 | 1 (12.5) | 0 | 1 (4.0) |
| Laryngeal pain | 0 | 1 (12.5) | 0 | 1 (4.0) |
| Any possibly related adverse events a | 0 | 0 | 1 (11.1) | 1 (4.0) |
As assessed by the investigator.
4. DISCUSSION
Balcinrenone is a novel selective non‐steroidal MRA with a differential mechanism of action relative to approved MRAs, under development as a fixed‐dose combination with the SGLT2i dapagliflozin for the treatment of HF with impaired kidney function and CKD. In Phase 1 studies in healthy male participants, single doses up to 1200 mg and multiple ascending doses up to 300 mg twice daily of balcinrenone have shown approximately dose‐proportional pharmacokinetics up to 200 mg. Balcinrenone has been well tolerated, and no safety concerns have been reported in PK trials. An acceptable safety profile was observed in a Phase 2b study of balcinrenone plus dapagliflozin in patients with HF and reduced kidney function. 9 , 11 , 12 , 13
In the present study, only minor effects of hepatic impairment on balcinrenone exposure were demonstrated. Compared with participants with normal hepatic function, AUC was similar in participants with mild hepatic impairment, whereas in participants with moderate hepatic impairment AUC was 1.3‐fold higher. No effects were seen on C max or t max in participants with neither mild nor moderate hepatic impairment. A previous mass balance study estimated that the fraction absorbed of an oral dose of balcinrenone is 94% and that the absolute bioavailability is 52%. Metabolism, primarily mediated by CYP3A4, is the main elimination pathway of balcinrenone. 13 Given this, a larger effect of hepatic impairment on the pharmacokinetics of balcinrenone could have been anticipated. However, data from the same mass balance study indicated that the presystemic metabolism of balcinrenone is mainly carried out in the gut, where CYP3A4 is abundant, and that the first‐pass hepatic metabolism is only 10%. 13 The effect of hepatic impairment on the bioavailability of orally administered drugs is mainly the result of reduced presystemic liver metabolism, whereas gut wall metabolism is affected to a lesser extent, 24 supporting limited effect of hepatic impairment on balcinrenone exposure.
In participants with moderately impaired hepatic function, the half‐life of balcinrenone increased twofold compared to participants with normal hepatic function, despite the very modest increase in AUC observed. A possible explanation is the flat nature of the end of the concentration–time plot for the moderate hepatic impairment group, where plasma concentrations of balcinrenone are close to the detection limit of 2.0 nmol/L.
Renal clearance of balcinrenone in the participants with normal hepatic function in this study was 2.6 L/h. This is lower than what was found in the mass balance study (5.6 L/h). 13 It is also lower than in the participants with normal renal function in the renal impairment study (5.3 L/h) who are more similar to the participants with normal hepatic function in the current study in terms of age, BMI and percentage females. 14 The variability (geometric CV%) for CL R was considerably higher (170%) among the participants with normal hepatic function compared with the participants with mild and moderate hepatic impairment (48% and 34%, respectively). Despite a low urine volume in two participants with normal hepatic function (<1 L during the 24‐h collection), urinary balcinrenone concentration in these two participants was comparable with those in other participants with normal hepatic function. It can thus not be excluded that some of the urinary output from these subjects was not collected and that the urinary clearance of balcinrenone was falsely low in participants with normal hepatic function in this study.
Protein binding of balcinrenone was similar among participants with mild and moderate hepatic impairment and participants with normal hepatic function in this study. The protein binding of 81.5% in the mass balance study 13 classifies balcinrenone as a drug with low plasma protein binding (<90%). For such drugs, changes in protein binding in hepatic impairment are anticipated to be low. 24 It should be mentioned, though, that in this study there was no evident decrease in serum concentrations of albumin among participants with impaired hepatic function, limiting the possibility to investigate differences in protein binding.
Although guidance on the investigation of pharmacokinetics in patients with impaired hepatic function recommend the use of CP classification to categorize the degree of hepatic impairment, it is acknowledged that this classification was not developed for the purpose of predicting drug elimination capacity, and that individual components of the CP classification such as serum levels of albumin and bilirubin and prothrombin time may sometimes be better related to drug elimination capacity. 18 , 19 In this study, our exploratory analyses did not find any significant correlation between any of the serum markers, or CP class, and the pharmacokinetic parameters investigated, although visual trends were seen for these serum markers including CP score and balcinrenone elimination.
A limitation of this study is its small sample size, which may limit the generalizability of the findings to a broader population. Most of the participants in the moderate hepatic impairment group had a score in the lower end of the CP Class B range of 7–9. It cannot be excluded that the impact of hepatic impairment on the pharmacokinetics of balcinrenone would have been larger if more participants with a higher score had been included. Additionally, the current study did not include subjects with severe hepatic impairment (CP C). However, given that patients with severe hepatic impairment and high CP scores are to a very large extent already treated with an MRA (spironolactone) due to ascites, with recommended doses for ascites treatment and prevention being higher than doses recommended for HF, 25 it is unlikely that the fixed‐dose combination of balcinrenone and dapagliflozin would be a relevant therapeutic option for patients with severe hepatic impairment once approved. In addition, dapagliflozin labels in some countries recommend a starting dose of 5‐mg dapagliflozin in patients with severe hepatic impairment, 16 whereas the fixed‐dose combination of balcinrenone and dapagliflozin is developed with dapagliflozin 10 mg. Therefore, we did not include patients with severe hepatic impairment, and no studies of balcinrenone are planned in this patient population. Patients with severe hepatic impairment are also excluded from ongoing studies with balcinrenone/dapagliflozin.
A single‐dose design is certainly a relevant limitation for a study investigating a population with a potentially impaired metabolism, like in the case of hepatic dysfunction. However, a single‐dose design is considered appropriate by regulators for the evaluation of pharmacokinetics of medicinal products with linear and time‐independent pharmacokinetics in patients with impaired hepatic function. 18 , 19 The previous multiple ascending dose study showed that at the dose investigated in the current study, accumulation of balcinrenone is minimal and the pharmacokinetics is linear and time‐independent. 11
5. CONCLUSION
In conclusion, balcinrenone exposure after a single oral dose of 50 mg was similar in participants with mild hepatic impairment compared with exposure in participants with normal hepatic function. In participants with moderate hepatic impairment, AUC, but not C max, was slightly increased. We do not consider the minor AUC increase seen in participants with moderate hepatic impairment to be clinically relevant. Thus, we do not recommend any dose adjustment for patients with mild or moderate hepatic impairment. Balcinrenone was well tolerated, and no new safety findings were observed.
AUTHOR CONTRIBUTIONS
A.L.E., D.K., B.T., J.H.‐G., M.L.‐Z. and H.E. contributed to designing the clinical trial and the study protocol. A.L.E., D.K., B.T., J.P., M.H., T.P., J.H.‐G., M.L.‐Z. and H.E. performed the research and conducted data analysis. A.L.E. and H.E. drafted the first version of the manuscript which was further developed by all authors. All authors reviewed and approved the final version of the manuscript.
CONFLICT OF INTEREST STATEMENT
All authors are employees or former employees of AstraZeneca and may hold stock or stock options.
Supporting information
Figure S1a Scatter plot and regression model for the slope of balcinrenone Cmax versus Child–Pugh score.
Figure S1b. Scatter plot and regression model for the slope of balcinrenone AUC last versus Child–Pugh score.
Figure S1c. Scatter plot and regression model for the slope of balcinrenone AUC inf versus Child–Pugh score.
Figure S1d. Scatter plot and regression model for the slope of balcinrenone apparent clearance versus Child–Pugh score.
Figure S2a. Scatter plot and regression model for the slope of balcinrenone C max versus serum bilirubin.
Figure S2b. Scatter plot and regression model for the slope of balcinrenone AUC last versus serum bilirubin.
Figure S2c. Scatter plot and regression model for the slope of balcinrenone AUC inf versus serum bilirubin.
Figure S2d. Scatter plot and regression model for the slope of balcinrenone apparent clearance versus serum bilirubin.
Figure S3a. Scatter plot and regression model for the slope of balcinrenone C max versus serum albumin.
Figure S3b. Scatter plot and regression model for the slope of balcinrenone AUC last versus serum albumin.
Figure S3c. Scatter plot and regression model for the slope of balcinrenone AUC inf versus serum albumin.
Figure S3d. Scatter plot and regression model for the slope of balcinrenone apparent clearance versus serum albumin.
Figure S4a. Scatter plot and regression model for the slope of balcinrenone C max versus prothrombin time.
Figure S4b. Scatter plot and regression model for the slope of balcinrenone AUC last versus prothrombin time.
Figure S4c. Scatter plot and regression model for the slope of balcinrenone AUC inf versus prothrombin time.
Figure S4d. Scatter plot and regression model for the slope of balcinrenone apparent clearance versus prothrombin time.
ACKNOWLEDGEMENTS
The authors would like to thank the participants, their families and the coordinating investigator Thomas C. Marbury and the principal investigators Eric J. Lawitz and Juan Carlos Rondon involved in this study. We thank the physicians and nurses who cared for the participants, and the biologists and technicians who analysed the samples.
Appendix 1. PROHIBITED MEDICATIONS
The following medications were prohibited for 10 h prior to and 10 h after study intervention:
phosphate binders (e.g., aluminium hydroxide and calcium carbonate)
acid reducing agents (e.g., ranitidine/nizatidine or proton pump inhibitors)
cholestyramine/colestipol
MRA agents (e.g., spironolactone, eplerenone and finerenone)
The following medications were prohibited within 2 weeks prior to study intervention or longer if the medication has a long half‐life:
| Use category | Type of medication/treatment | Additional information |
|---|---|---|
| Prohibited and/or restricted | Strong inhibitors of CYP3A4 | Boceprevir, cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, telithromycin, troleandomycin and voriconazole |
| Strong inducers of CYP3A4 | Nevirapine, rifampicin, carbamazepine, fosphenytoin, pentobarbital, phenobarbital, phenytoin, primidone, rifapentine, enzalutamide, lumacaftor, St. John's Wort, mitotane, apalutamide, rimexolone, rifamycin, topiramate, Qsymia, oxcarbazepine and midostaurin | |
| Moderate inhibitors of CYP3A4 | Aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, quinine, fluconazole, fluvoxamine, imatinib, tofisopam and verapamil | |
| Moderate inducers of CYP3A4 | Bosentan, efavirenz, etravirine, phenobarbital and primidone | |
| Cyclosporin or tacrolimus | ||
| Macrolide antibiotics | Clarithromycin and telithromycin | |
| Chloramphenicol (antibiotic) | ||
| Nefazodone (antidepressant) |
Abbreviation: CYP = cytochrome P450.
Eriksson AL, Karsanji D, Tuyishimire B, et al. The effect of mild and moderate hepatic impairment on the pharmacokinetics, safety and tolerability of balcinrenone. Br J Clin Pharmacol. 2026;92(10):3656‐3665. doi: 10.1002/bcp.70670
Funding information The trial was funded by AstraZeneca.
DATA AVAILABILITY STATEMENT
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1a Scatter plot and regression model for the slope of balcinrenone Cmax versus Child–Pugh score.
Figure S1b. Scatter plot and regression model for the slope of balcinrenone AUC last versus Child–Pugh score.
Figure S1c. Scatter plot and regression model for the slope of balcinrenone AUC inf versus Child–Pugh score.
Figure S1d. Scatter plot and regression model for the slope of balcinrenone apparent clearance versus Child–Pugh score.
Figure S2a. Scatter plot and regression model for the slope of balcinrenone C max versus serum bilirubin.
Figure S2b. Scatter plot and regression model for the slope of balcinrenone AUC last versus serum bilirubin.
Figure S2c. Scatter plot and regression model for the slope of balcinrenone AUC inf versus serum bilirubin.
Figure S2d. Scatter plot and regression model for the slope of balcinrenone apparent clearance versus serum bilirubin.
Figure S3a. Scatter plot and regression model for the slope of balcinrenone C max versus serum albumin.
Figure S3b. Scatter plot and regression model for the slope of balcinrenone AUC last versus serum albumin.
Figure S3c. Scatter plot and regression model for the slope of balcinrenone AUC inf versus serum albumin.
Figure S3d. Scatter plot and regression model for the slope of balcinrenone apparent clearance versus serum albumin.
Figure S4a. Scatter plot and regression model for the slope of balcinrenone C max versus prothrombin time.
Figure S4b. Scatter plot and regression model for the slope of balcinrenone AUC last versus prothrombin time.
Figure S4c. Scatter plot and regression model for the slope of balcinrenone AUC inf versus prothrombin time.
Figure S4d. Scatter plot and regression model for the slope of balcinrenone apparent clearance versus prothrombin time.
Data Availability Statement
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.