Indications
Seladelpar is approved for the treatment of primary biliary cholangitis (PBC) in adults. It can be used in conjunction with ursodeoxycholic acid (UDCA) for individuals who have shown an inadequate response to UDCA. Additionally, it is suitable as a standalone therapy for patients who are unable to tolerate UDCA. However, its use is currently approved under accelerated approval and may be subject to future revisions. Patients with or who develop decompensated cirrhosis, such as those experiencing ascites, variceal bleeding, or hepatic encephalopathy, are advised against the use of seladelpar.
Pharmacodynamics
Seladelpar functions by reducing the levels of total bile acids and limiting bile acid synthesis in patients with PBC. Elevated concentrations of bile acids in hepatobiliary disorders, including PBC, are thought to increase alkaline phosphatase (ALP) levels. In clinical studies, patients with PBC who were administered 10 mg of seladelpar once daily exhibited a significant reduction in mean ALP from baseline as early as one month into treatment, in contrast to the placebo group. This lowered ALP was generally maintained through the 12th month. Another study demonstrated a dose-dependent reduction in mean ALP with seladelpar doses of 2, 5, or 10 mg administered once daily.
Absorption
Upon administration of a single dose, the systemic exposure of seladelpar increased proportionally with doses ranging from 2 mg (0.2 times the recommended dose) to 15 mg (1.5 times the recommended dose) and greater than proportionally at higher doses. With an increase from 10 mg to 200 mg (20 times the recommended dose), the mean Cmax and mean AUC rose 70-fold and 27-fold, respectively. Following once-daily dosing, seladelpar reached steady-state by day 4, with less than a 30% increase in AUC. In patients with PBC, the mean Cmax and AUC at steady-state for a 10 mg daily dose were 103 ng/mL and 902 ng·h/mL, respectively. The median time to reach peak concentration (Tmax) was observed to be 1.5 hours. Importantly, the pharmacokinetics of seladelpar were not significantly altered when administered with a high-fat meal in healthy subjects.
Metabolism
Seladelpar undergoes primary metabolism by the enzyme CYP2C9 and to a lesser extent by CYP2C8 and CYP3A4. This metabolic process leads to the formation of three major metabolites: seladelpar sulfoxide (M1), desethyl-seladelpar (M2), and desethyl-seladelpar sulfoxide (M3). The metabolite-to-parent AUC ratios were determined to be 0.36, 2.32, and 0.63 for M1, M2, and M3, respectively. The median Tmax for these metabolites were 10 hours for M1 and 4 hours for both M2 and M3. Notably, none of these major metabolites exhibit pharmacological activity.
Mechanism of Action
Seladelpar functions as a selective agonist of peroxisome proliferator-activated receptor-delta (PPARδ), though its precise mechanism of action in treating primary biliary cholangitis (PBC) remains incompletely characterized. Its pharmacological activity is thought to involve the inhibition of bile acid synthesis mediated through PPARδ activation, which is of clinical relevance. Research indicates that seladelpar's action on PPARδ leads to a reduction in bile acid production by inducing Fibroblast Growth Factor 21 (FGF21). This induction stimulates the c-Jun N-terminal kinase (JNK) signaling pathway, resulting in the downregulation of CYP7A1, the key enzyme involved in converting cholesterol into bile acids. Notably, seladelpar's ability to inhibit bile acid synthesis appears to operate independently of the farnesoid X receptor (FXR) pathway, another significant mechanism controlling bile acid production in the liver.
