Abstract: FR-PO220
Preclinical Pharmacokinetics of a Novel Nicorandil Prodrug
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
- Gupta, Pramod, Unicycive Therapeutics Inc., Los Altos, California, United States
- Khare, Atul, Unicycive Therapeutics Inc., Los Altos, California, United States
Background
Nicorandil, a potassium channel activator, is used to prevent or reduce angina. Limitations of nicorandil include serious gastrointestinal side effects and rapid absorption and elimination. A nicorandil prodrug may increase short half-life and improve safety profile of nicorandil. We present pharmacokinetic data in dogs for a novel nicorandil prodrug(UNI-494).
Methods
Groups of 3 beagle dogs were administered a single oral dose of 3, 10, or 30mg/kg UNI-494 at a volume of 5mL/kg. Clinical observations were recorded at approximately 1, 1.5, 2, 3, and 24h post-dose. Whole blood samples were collected pre-dose and 0.083, 0.25, 0.50, 1, 1.5, 2, 4, 8, and 24h post-dose to analyze systemic exposure to UNI-494and nicorandil. Dose and concentration parameters(Cmax and AUC) were used to generate linearity plots and calculate the coefficients of determination(r2) and slopes for UNI-494 and nicorandil.
Results
Mean Tmax, Cmax, and AUC of 3, 10, and 30mg/kg dose groups are displayed in Table 1. For the linearity plots, r2 values and slopes for dose vs. Cmax and dose vs. AUC are shown in Figures 1 and 2, respectively.
Conclusion
Nicorandil was rapidly formed from the prodrug UNI-494. Mean Cmax for nicorandil was >5-fold greater than that of UNI-494, demonstrating efficient conversion of the prodrug to active drug. The conversion was consistent across dose groups. These results indicate that UNI-494 is a rationally designed drug, and future studies should evaluate this promising treatment in the target population of patients with AKI.
Cmax, Tmax, and AUC by Dose Group and Analytes
| Dose Group (mg/kg) | Analyte | Cmax (ng/mL) | Tmax (Hour) | AUC (Hour*ng/mL) |
| 3 | UNI-494 | 43 | 0.3 | 34 |
| Nicorandil | 1,300 | 0.7 | 3,400 | |
| 10 | UNI-494 | 178 | 0.3 | 162 |
| Nicorandil | 3,070 | 1.5 | 11,400 | |
| 30 | UNI-494 | 1,500 | 0.3 | 1,510 |
| Nicorandil | 7,530 | 1.3 | 38,000 |