Sparsentan

Sparsentan is a single molecule with antagonism of the endothelin type A receptor (ET_AR) and the angiotensin II type 1 receptor (AT₁R). Sparsentan has high affinity for both the ET_AR (Ki=12.8 nM) and the AT₁R (Ki=0.36 nM), and greater than 500-fold selectivity for these receptors over the endothelin type B and angiotensin II subtype 2 receptors. Endothelin-1 and angiotensin II are thought to contribute to the pathogenesis of IgAN via the ET_AR and AT₁R, respectively.

Dose-response information is not available. At the recommended dose regimen, no statistically significant exposure-response (E-R) relationship was identified between sparsentan exposure and the percentage reduction from baseline in UPCR at Week 36 over the observed sparsentan exposure range. No clinically meaningful E-R relationships were observed for hypotension of any grade and peripheral edema worst grade. A statistically significant relationship was observed between sparsentan exposures and the incidence of hyperkalemia of any grade.

Cardiac Electrophysiology

In a randomized, positive-, and placebo-controlled study in healthy subjects, sparsentan caused QTcF prolongation with maximal mean effect of 8.8 msec (90% CI: 5.9, 11.8) at 800 mg and 8.1 msec (90% CI: 5.2, 11.0) at 1600 mg. The underlying mechanism behind the observed QTc prolongation is unknown but is unlikely to be mediated via direct inhibition of hERG channels. At the recommended dose, no clinically relevant QTc prolongation (i.e., >20 msec) is expected.

The pharmacokinetics of sparsentan are presented as geometric mean (% coefficient of variation) unless otherwise specified. The C_max and AUC of sparsentan increase less than proportionally following administration of single doses of 200 mg to 1600 mg. Sparsentan showed time-dependent pharmacokinetics which may be related to the drug inducing its own metabolism over time. Steady-state plasma levels are reached within 7 days with no accumulation of exposure at the approved recommended dosage. Following a single oral dose of 400 mg sparsentan, the mean C_max and AUC are 6.97 μg/mL and 83 μg×h/mL, respectively. Following daily doses of 400 mg sparsentan, the steady-state mean C_max and AUC are 6.47 μg/mL and 63.6 μg×h/mL, respectively.

Absorption

Following a single oral dose of 400 mg sparsentan, the median (minimum to maximum) time to peak plasma concentration is approximately 3 hours (2 to 8 hours).

Effect of Food

Sparsentan AUC and C_max increased by 22% and 108%, respectively, following administration of a single oral 800 mg dose with a high fat, high calorie meal (1000 kcal, 50% fat). No clinically significant differences in sparsentan pharmacokinetics were observed following administration of a single 200 mg dose with a high fat, high calorie meal.

Distribution

The apparent volume of distribution at steady state is 61.4 L at the approved recommended dosage.

Sparsentan is >99% bound to human plasma proteins.

Elimination

The clearance of sparsentan is time-dependent which may be related to the drug inducing its own metabolism over time. The apparent clearance (CL/F) of sparsentan is 3.88 L/h following the initial 400 mg dose then increases to 5.11 L/h at steady state.

The half-life of sparsentan is estimated to be 9.6 hours at steady state.

Metabolism

Cytochrome P450 3A is the major isozyme responsible for the metabolism of sparsentan.

Excretion

After a single dose of radiolabeled sparsentan 400 mg to healthy subjects, approximately 80% of the dose was recovered in feces (9% unchanged) and 2% in urine (negligible amount unchanged). 82% of the dosed radioactivity was recovered within a 10-day collection period.

Specific Populations

No clinically significant differences in the pharmacokinetics of sparsentan were observed based on age (18–73 years), sex, race, mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m²), or mild to moderate hepatic impairment (Child-Pugh class A or B). Patients with severe hepatic impairment (Child-Pugh class C) and eGFR <30 mL/min/1.73 m² have not been studied.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effect of Other Drugs on Sparsentan:

Strong CYP3A inhibitors: Concomitant use with itraconazole (strong CYP3A inhibitor) increased sparsentan C_max by 25% and AUC by 174%.

Moderate CYP3A inhibitors: Concomitant use with cyclosporine (moderate CYP3A inhibitor) increased sparsentan C_max by 41% and AUC by 70%.

Strong CYP3A inducers: Coadministration of rifampin (strong CYP3A inducer) is predicted to decrease sparsentan C_max by 23% and AUC_0-inf by 47% at steady state.

Effect of Sparsentan on Other Drugs:

No clinically significant differences in the pharmacokinetics of midazolam (sensitive CYP3A4 substrate) or pitavastatin (OATP1B1, OATP1B3, P-gp, and BCRP substrate) were observed when co-administered with sparsentan. In addition, sparsentan had no clinically significant effect on serum creatinine levels (an endogenous biomarker of OAT2, OCT2, MATE1, and MATE2K) or on 6β hydroxycortisol (an endogenous biomarker of OAT3).

CYP2B6 substrates: Concomitant use with sparsentan decreased the exposure of bupropion (CYP2B6 substrate) C_max by 32% and AUC by 33%.

In vitro Studies

CYP Enzymes: Sparsentan is a substrate of CYP3A. Sparsentan is both an inhibitor and inducer of CYP3A and an inducer of CYP2B6, CYP2C9, and CYP2C19.

Transporters: Sparsentan is a substrate of P-gp and BCRP but is not a substrate of OATP1B1 or OATP1B3. Sparsentan is an inhibitor of P-gp, BCRP, OATP1B3 and OAT3 but does not inhibit MRP, OATP1B1, NTCP, OCT2, OAT1, MATE1, or MATE2K at relevant concentrations.