Abstract: FR-PO217
Effect of Multiple Doses of Sparsentan on the Single-Dose Pharmacokinetics of Dapagliflozin: Open-Label Drug-Drug Interaction Study in Healthy Adults
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
- Chen, Charles, Travere Therapeutics Inc, San Diego, California, United States
- Cai, Danlin, Travere Therapeutics Inc, San Diego, California, United States
- Winnett, Claire E., Travere Therapeutics Inc, San Diego, California, United States
- Verma, Neeraj, Travere Therapeutics Inc, San Diego, California, United States
- Preciado, Priscila, Travere Therapeutics Inc, San Diego, California, United States
Background
Sparsentan (SPAR) is a novel single molecule Dual Endothelin Angiotensin Receptor Antagonist (DEARA) being investigated for immunoglobulin A nephropathy and focal segmental glomerulosclerosis. Potential drug-drug interactions (DDI) with sodium-glucose co-transporter 2 inhibitors are not known. This phase 1 study examined the effect of multiple doses of SPAR on the pharmacokinetics (PK) of single-dose dapagliflozin (DAPA) and assessed the safety and tolerability of single-dose DAPA when co-administered after multiple doses of SPAR in healthy adults.
Methods
This open-label DDI study included Period 1 (Days 1-5; single dose of 10mg DAPA on Day 1, PK sampling pre-dose and up to 96 hours post-dose) and Period 2 (Days 5-14; 800mg SPAR once daily for 10 days with single 10mg dose DAPA co-administered on Day 11, DAPA PK sampling pre-dose and up to 96 hours after Day 11 dosing). To avoid hypoglycemic events, subjects received an oral 20% glucose solution in water with the DAPA dose and every ~15 minutes up to 4 hours post-dose. Plasma concentrations and PK parameters of DAPA and SPAR were summarized. Subjects with evaluable data for both periods were included in an ANOVA mixed model analysis of DAPA AUC0-t, AUC0-inf, and Cmax following DAPA+SPAR vs DAPA alone. Treatment-emergent adverse events (TEAEs) were summarized.
Results
Twenty-two healthy adults were enrolled and 20 completed both study periods. Mean peak and extent of DAPA exposure (Cmax and AUC) values were similar following 10mg DAPA alone and 10mg DAPA+800mg SPAR (Table). TEAEs were reported by 14 (63.6%) subjects. Most frequent were headache (6; 27.3%), nausea (5; 22.7%), and preprandial asymptomatic hypoglycemia (5; 22.7%).
Conclusion
Multiple dosing of SPAR did not affect single-dose DAPA PK in healthy adults. Single-dose DAPA co-administered with multiple doses of SPAR appeared to be well tolerated by healthy adults.
Plasma Dapagliflozin PK Parameters Following Dapagliflozin+Sparsentan Versus Dapagliflozin Alone
| Dapagliflozin+Sparsentan | Dapagliflozin | ||||
| Geometric LSMs | Geometric LSMs | GLSMR (%) | 90% CI | Intra-subject CV% | |
| AUC0-t (ng*hr/mL) | 526.1 (n=20) | 508.8 (n=20) | 103.4 | 99.9-107.0 | 6.3 |
| AUC0-inf (ng*hr/mL) | 565.4 (n=16) | 533.7 (n=16) | 105.9 | 103.1-108.9 | 4.4 |
| Cmax (ng/mL) | 79.9 (n=20) | 73.9 (n=20) | 108.2 | 96.0-121.8 | 22.0 |
Funding
- Commercial Support – Travere Therapeutics, Inc., San Diego, CA