032: The Effect of an Acid-reducing Agent, Esomeprazole on Sparsentan Pharmacokinetics in Healthy Volunteers

Statement of Purpose, Innovation or Hypothesis: Immunoglobulin A nephropathy (IgAN) is a severe autoimmune disease with a progression to end-stage renal disease in 20% to 40% of patients within 10 to 20 years post-diagnosis. A promising therapeutic approach is Sparsentan, a novel and potent orally active dual blocker of angiotensin II type 1 and endothelin type A receptors. Sparsentan is a poorly soluble ampholyte with pH-dependent solubility. To assess the potential impact of gastric pH on Sparsentan’s pharmacokinetic (PK) profile, we employed a physiologically based pharmacokinetic modeling approach (PBPK). Based on PBPK predictions, we investigated the drug-drug interaction (DDI) between Sparsentan and Esomeprazole, an acid-reducing agent (ARA) in a Phase I study.

Description of Methods & Materials: A bottom-up PBPK model for Sparsentan (SimCyp v19, Certara, London, UK) was employed to predict the effect of gastric pH on Sparsentan's PK. Simulations were conducted considering physiological gastric pH value under fasted condition of 1.5 and at a pH of 5. Based on the PBPK results, DDI study between Sparsentan and Esomeprazole was conducted. Esomeprazole is a proton pump inhibitor (PPI) and can maintain intragastric pH above 4.0 for most of the steady state . A Phase I, two-treatment, fixed-sequence study with an open-label design was conducted to assess the impact of ARA on the PK profile of Sparsentan in 20 healthy adult male and female participants. Individuals received a single 800 mg dose of Sparsentan on Day 1. Following a 7-day washout period, participants received Esomeprazole (40mg) once daily, for 6 days (Day 8-13). On Day 13, a single 800 mg dose of Sparsentan was co-administered with Esomeprazole. PK samples were collected after each treatment sequence. Non-compartmental analysis was performed using Phoenix WinNonlin v8.4 (Certara, London, UK) to calculate Sparsentan PK parameters. The analysis of variance (ANOVA) model utilizing SAS® v9.4 or higher was employed to evaluate the impact of Esomeprazole on Sparsentan's PK. The ANOVA model computed the least squares geometric mean values (LSM) for maximum plasma concentration (Cmax), area under the curve up to 24 hr and to infinity (AUC_0-24hr, AUC_0-inf), alongside the ratio between treatment LSMs and the 90% confidence interval (CI) of the ratio of LSMs. A drug interaction was considered present if the 90% CI of the ratio of LSMs between two treatments fell outside the predetermined interval of 80–125%.

Data & Results: The PBPK predicted that elevating the stomach pH from 1.5 to 5 resulted in a reduction of 37.1% and 32.5% in the geometric mean values of Sparsentan's Cmax and AUC0-inf, respectively. Phase I study results showed that Sparsentan single dose exhibited mean values of Cmax, AUC_0-24hr and AUC_0-inf of 7,154 ng/mL, 95,210 hr*ng/mL and 163,000 hr*ng/mL, respectively. In the presence of Esomeprazole, Sparsentan exhibited Cmax, AUC_0-24hr and AUC >_0-inf of 6,512 ng/mL, 86,500 hr*ng/mL and 175,800 hr*ng/mL, respectively. The 90% CI of the ratio of LSM of Cmax, AUC_0-24hr and AUC_0-inf between the 2 treatments fell within 80% and 125%.

Interpretation, Conclusion or Significance: Based on the pH dependent DDI study, it can be concluded that Sparsentan PK will not be affected in presence of ARA.

Disclosures: All authors are employees and shareholders of Travere Therapeutics Inc.

Citations/References: Miner P, Katz PO, Chen Y, Sostek M, 2003, Gastric Acid Control With Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, and Rabeprazole: A Five-Way Crossover Study, Am J Gastronenterol, 98(12):2616-20.

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