Physiologically-Based Pharmacokinetic Model of Sparsentan to Evaluate Drug-Drug Interaction Potential
Clinical Pharmacology and Therapeutics Pharmacometrics & Systems Pharmacology – 2023
Effect of Multiple Doses of Sparsentan on the Single-Dose Pharmacokinetics of Dapagliflozin: An Open-Label Drug–Drug Interaction Study in Healthy Adults
Journal article
Published on February 28, 2023
Contributors:
Chen SC, Cai D, Winnett C et al.
Chen SC, Cai D, Winnett C et al.
DOI:
10.1002/cpdd.1231
10.1002/cpdd.1231
Summary
Drug–drug interactions (DDI) between sparsentan and dapagliflozin were assessed in healthy adults1
Background
Sparsentan is a novel dual antagonist of the endothelin type A receptor and angiotensin II type 1 receptor for chronic kidney disease (CKD).1-3 Sparsentan is predominantly metabolized via cytochrome P450 (CYP) 3A, and it is a competitive inhibitor and inducer of CYP3A in vitro.1
Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor (SGLT2i) that is indicated for CKD.4 Dapagliflozin is primarily metabolized by uridine 5-diphospho-glucuronosyltransferase 1A9 (UGT1A9).5
Potential drug–drug interactions (DDIs) of sparsentan and dapagliflozin are of interest; the effect of sparsentan on UGT1A9 is unknown.1
Aim
The aim of this study was to evaluate the effect of multidose sparsentan on the pharmacokinetics (PK) of single-dose dapagliflozin and assess the safety and tolerability of coadministration in healthy adults.1
Approach
This was an open-label 1-sequence crossover DDI study of sparsentan and dapagliflozin that included 22 healthy adults (22-55 years), 20 of whom completed the treatment sequence.1 The study comprised two periods1:
Period 1 (Days 1-5)
- Participants received 10 mg dapagliflozin (Day 1)1
Period 2 (Days 5-14)
- 800 mg sparsentan daily (Days 5-14)1
- One 10 mg dose of dapagliflozin (Day 11)1
All drugs were administered orally after at least a 10-hour fast.1 PK samples were collected before and after treatments throughout the study.1
Findings
Pharmacokinetics
Sparsentan did not affect PK of dapagliflozin1
Mean peak plasma concentration (Cmax) and exposure (area under the curve [AUC]) were similar after administration of 10 mg dapagliflozin and after 10 mg dapagliflozin + 800 mg sparsentan1:
10 mg dapagliflozin1:
- Cmax: 75 ng/mL
- AUC0–inf: 539 ng • h/mL
10 mg dapagliflozin + 800 mg sparsentan1:
- Cmax: 84 ng/mL
- AUC0–inf: 579 ng • h/mL
PK data were similar for Cmax and AUC of dapagliflozin-3-O-glucuronide, an inactive metabolite of dapagliflozin, suggesting that sparsentan had minimal inhibitory or inductive effects on UGT1A9.1
Safety and tolerability
Forty-nine treatment-emergent adverse events (TEAEs) were reported by 14 (63.6%) participants after drug exposure.1
- Dapagliflozin alone: 4 (18.2%)1
- Sparsentan alone: 5 (23.8%)1
- Dapagliflozin + sparsentan: 11 (52.4%)1
The most common TEAEs reported were headache (n=6; 27.3%) and nausea (n=5; 22.7%).1 Sparsentan alone was associated with preprandial asymptomatic hypoglycemia.1 The majority of TEAEs were mild and no serious or unusual adverse events (AEs) were reported.1
Key takeaway
Results suggest that in healthy adults, PK of dapagliflozin are not affected by daily sparsentan, and coadministration appears safe and well-tolerated.1 There does not appear to be a DDI between sparsentan and dapagliflozin in healthy patients.1 Further research is needed to establish the efficacy and safety of coadministration of dapagliflozin and sparsentan in patients with kidney disease.1
Related Content
Physiologically-Based Pharmacokinetic Model of Sparsentan to Evaluate Drug-Drug Interaction Potential
Clinical Pharmacology and Therapeutics Pharmacometrics & Systems Pharmacology – 2023
Footnotes
As of September 2024, sparsentan is not FDA-approved for the treatment of FSGS.
AUC, area under the curve; CKD, chronic kidney disease; Cmax: peak plasma concentration; CYP, cytochrome P450; DDI, drug-drug interaction; FSGS, focal segmental glomerulosclerosis; IgA, immunoglobulin A; PK, pharmacokinetic; SGLT2i, sodium-glucose cotransporter 2 inhibitor; TEAE, treatment-emergent adverse event; UGT1A9, uridine 5-diphospho-glucuronosyltransferase 1A9.
- Chen SC et al. Clin Pharmacol Drug Dev. 2023;12(5):535-541.
- Komers R et al. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R877-R884.
- Komers R et al. Kidney Int Rep. 2017;2(4):654-664.
- FARXIGA® (dapagliflozin) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP. 06/2024
- Kasichayanula S et al. Clin Pharmacokinet. 2014;53(1):17-27.
- Boeckhaus J, Gross O. Cells. 2021;10(7):1815.
- Wheeler DC et al. Nephrol Dial Transplant. 2022;37(9):1647-1656.
- Wheeler DC et al. Kidney Int. 2021;100(1):215-224.
MA-SP-24-0105 | September 2024