Molecular mass: 592.76 g/mol PubChem compound: 10257882
Sparsentan is a dual endothelin angiotensin receptor antagonist.
It is a single molecule that functions as a high affinity, dual-acting antagonist of both the ETAR and AT1R. Endothelin 1, via ETAR, and angiotensin II, via AT1R, mediate processes that lead to IgAN progression through haemodynamic actions and mesangial cell proliferation, increased expression and activity of proinflammatory and profibrotic mediators, podocyte injury, and oxidative stress. Sparsentan inhibits activation of both ETAR and AT1R and thereby reduces proteinuria and slows the progression of kidney disease.
In a randomised, positive- and placebo-controlled study with healthy subjects, sparsentan caused mild QTcF prolongation with a peak effect of 8.8 ms (90% CI: 5.9, 11.8) at 800 mg and 8.1 ms (5.2, 11.0) at 1600 mg. In an additional study with healthy subjects, at sparsentan exposure exceeding exposure at maximum recommended human dose by more than 2-fold, the peak effect was 8.3 (6.69, 9.90) ms. Therefore, it is unlikely that sparsentan has a clinically relevant effect on QT prolongation.
Following a single oral dose of 400 mg sparsentan, the median time to peak plasma concentration is approximately 3 hours.
Following a single oral dose of 400 mg sparsentan, the geometric mean Cmax and AUC are 6.97 μg/mL and 83 μg × h/mL, respectively. Steady-state plasma levels are reached within 7 days with no accumulation of exposure at the recommended dosage.
Following a dose of 400 mg sparsentan daily, the steady-state geometric mean Cmax and AUC are 6.47 μg/mL and 63.6 μg × h/mL, respectively.
At doses of 400 mg and below, the effect of a high fat meal on sparsentan exposure was not clinically relevant. Sparsentan can be taken with or without food.
Based on population pharmacokinetic analysis, the apparent volume of distribution at steady state is 61.4 L.
Sparsentan is highly bound (>99%) to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein.
Sparsentan is primarily metabolised by CYP3A4 with a minor contribution of CYP2C8, 2C9 and 3A5. Parent compound is the predominant entity in human plasma, representing approximately 90% of the total radioactivity in circulation. A minor hydroxylated metabolite was the only metabolite in plasma that accounted for >1% of the total radioactivity (approximately 3%). The main metabolic pathway of sparsentan was oxidation and dealkylation, and 9 metabolites were identified in human faeces, plasma and urine.
The clearance of sparsentan is time dependent. Based on population pharmacokinetic analysis, the apparent clearance is 3.88 L/h, increasing to 5.11 L/h at steady state.
The half-life of sparsentan at steady state is estimated to be 9.6 hours.
Following a single 400 mg dose of radiolabelled sparsentan, 82 % of the dosed radioactivity was recovered within a 10 day collection period: 80 % via the faeces with 9 % as unchanged, and 2 % via the urine with a negligible amount as unchanged.
The Cmax and AUC of sparsentan increase less than proportionally following administration of single doses of 200 mg to 1600 mg. Sparsentan showed time-dependent pharmacokinetics with no Cmax accumulation and decreased AUC at steady state following a dose of 400 or 800 mg daily.
Population pharmacokinetic analysis found no significant effect of age on the plasma exposure of sparsentan. No dosage adjustment is necessary for elderly patients. Sparsentan has not been studied in patients >75 years of age.
In a dedicated hepatic impairment study, systemic exposure following a single dose of 400 mg sparsentan was similar in patients with baseline mild or moderate hepatic impairment (Child-Pugh A or Child-Pugh B classification) compared to patients with normal hepatic function. No dose adjustment is required in patients with mild or moderate hepatic impairment. Sparsentan should be used with caution in patients with moderate hepatic impairment.
No data are available in patients with severe hepatic impairment and sparsentan is therefore not recommended in these patients (Child-Pugh C classification).
Based on population pharmacokinetic analysis in chronic kidney disease patients with mild (creatinine clearance 60 to 89 mL/min), moderate (creatinine clearance 30 to 59 mL/min), and severe (creatinine clearance 15 to 29 mL/min) kidney disease, there is no clinically meaningful effect of kidney impairment on pharmacokinetics as compared to normal kidney function (creatinine clearance ≥90 mL/min). No data are available in patients with end-stage kidney disease (creatinine clearance <15 mL/min).
Based on limited available data, no dose adjustment can be recommended for patients with severe kidney disease (eGFR <30 mL/min/1.73 m²). Sparsentan has not been studied in patients with severe kidney disease or undergoing dialysis, therefore sparsentan is not recommended in these patients. Sparsentan has not been studied in patients who have received a kidney transplant, therefore in this patient population sparsentan should be used with caution.
Population pharmacokinetic analyses indicate that there is no clinically meaningful effect of age, gender, or race on the pharmacokinetics of sparsentan.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction, and juvenile development.
Adverse reactions not observed in clinical studies but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:
In embryo-foetal development studies in rat and rabbit, developmental toxicity was seen in both species. In rats, dose-dependent teratogenic effects in the form of craniofacial malformations, skeletal abnormalities, increased embryo-foetal lethality, and reduced foetal weights were observed at all doses of sparsentan tested at exposures 8-fold and 13-fold over the AUC for 800 mg/day and 400 mg/day in humans. In rabbits, there were no foetal malformations or effects on embryo-foetal viability or foetal growth, but an increase in skeletal variations (supernumerary cervical ribs) occurred at an exposure of approximately 0.10 and 0.2 times the AUC in humans at 800 mg/day and 400 mg/day.
In the pre- and postnatal development study in rat, maternal toxicity including death was seen at ~8-fold and 13-fold, and maternal toxicity at ~2-fold and 3-fold the AUC in humans at 800 mg/day and 400 mg/day. An increase in pup deaths and decreased growth occurred at ~8-fold and 13-fold, and decreased growth at ~2-fold and 3-fold the AUC in humans at 800 mg/day and 400 mg/day.
Juvenile animal studies in rats demonstrated that there were no general toxicological adverse effects seen up to 10 mg/kg/day and no reproductive toxicity in males or females up to 60 mg/kg/day when dosing started on postnatal day (PND) 14 (equivalent to 1 year old children). Vascular toxicity occurred at doses ≥3 mg/kg/day when dosing started on PND 7 (equivalent to newborn infants).
Conclusions of studies for sparsentan show that sparsentan is considered not to be persistent, bioaccumulative and toxic (PBT) nor very persistent and very bioaccumulative (vPvB). A risk to the sewage treatment plant, surface water, groundwater, sediment and terrestrial compartment is not anticipated based on the prescribed use of sparsentan.
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