Abstract: FR-PO241
Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist KBP-5074 in Individuals With Moderate Hepatic Impairment
Session Information
- Pharmacology
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics‚ -Dynamics‚ -Genomics)
- 1900 Pharmacology (PharmacoKinetics‚ -Dynamics‚ -Genomics)
Authors
- McCabe, James Carden, Kbp Biosciences Co Ltd, Jinan, China
- Benn, Vincent, Kbp Biosciences Co Ltd, Jinan, China
- Zhang, Jay, Kbp Biosciences Co Ltd, Jinan, China
- Yang, Y. Fred, Kbp Biosciences Co Ltd, Jinan, China
Background
KBP-5074 is a selective nonsteroidal mineralocorticoid receptor antagonist. This study assessed the effect of moderate hepatic impairment on the pharmacokinetics, safety, and tolerability of KBP-5074.
Methods
This was an open, nonrandomized, multicenter, study investigating the PK, safety, and tolerability of a single oral dose of 0.5 mg KBP-5074 to male and female subjects with moderate hepatic impairment (Child-Pugh B score 7-9) compared to normal healthy subjects. Twelve subjects (6 subjects with moderate impairment and 6 matched healthy control subjects) were enrolled. All subjects received a single oral dose of 0.5 mg KBP-5074 on Day 1 after an overnight fast of ≥10 hours. Each healthy control subject was matched by age (±10 years), BMI (±20%), and sex to a moderate hepatic impairment subject. Serial blood collections were obtained through 264 hours postdose for plasma levels of KBP-5074. Plasma protein binding was analyzed and safety and tolerability were monitored.
Results
Following a single oral dose of 0.5 mg, KBP-5074 was steadily absorbed with median Tmax values of 4.00 and 3.00 hours, respectively. After reaching Cmax, the disposition of KBP-5074 appeared to be biphasic. The geometric mean t1/2 values for the moderate hepatic impairment group and normal healthy control group were 75.6 and 65.7 hours, respectively. Systemic exposure to KBP-5074 as assessed by AUC was 23.5% to 26.6% lower in subjects with moderate hepatic impairment versus healthy subjects, whereas Cmax was 41.2 % lower. KBP-5074 was determined to be >99.7% bound to proteins in plasma. Given the low percentage of unbound drug, it was not deemed appropriate to calculate the PK parameters for unbound drug. KBP-5074 was safe and well tolerated in all participants.
Conclusion
Small decreases of AUC and Cmax upon systemic exposure to KBP-5074 in subjects with moderate hepatic impairment demonstrate low hepatic extraction and is consistent with the observation that KBP-5074 is cleared predominantly in the gastrointestinal tract vs the kidney.
Considering the long half-life and small decrease in AUC and Cmax, a dose adjustment does not appear to be warranted in patients with moderate hepatic impairment.
Funding
- Commercial Support –