Seladelpar

Seladelpar is a peroxisome proliferator-activated receptor delta (PPARδ) agonist, or delpar. PPARδ is a nuclear receptor expressed in the liver and other tissues. PPARδ activation reduces bile acid synthesis in the liver through Fibroblast Growth Factor 21 (FGF21)-dependent downregulation of CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol and by decreasing cholesterol synthesis and absorption. These actions result in lower bile acid exposure in the liver and reduced circulating bile acid levels.

In clinical studies, reduction in ALP was observed within 1 week, continued to decrease through Month 3, and was sustained through Month 24.

In RESPONSE, treatment with seladelpar led to a decrease in Interleukin-31 (IL-31) after 6 and 12 months of treatment in patients with moderate to severe pruritus.

Absorption

Following oral administration of a single dose of seladelpar 10 mg, seladelpar was readily absorbed with median time to peak concentration (t_max) of approximately 1.5 hours.

Seladelpar exposure increased approximately dose-proportionally with single doses from 2 mg to 15 mg, after which the increase in C_max was larger than dose-proportional.

Seladelpar showed no evidence of meaningful drug accumulation after multiple daily dosing, and steady-state was achieved from day 4 onwards after daily dosing.

Co-administration of seladelpar with food delayed the t_max by 2.5 hours relative to fasted conditions and resulted in an approximately 32% reduction in the C_max of seladelpar. As the overall exposure (AUC) is similar, the effects of food on seladelpar pharmacokinetics are not considered clinically relevant.

Distribution

In PBC patients, the steady state apparent volume of distribution of seladelpar is approximately 110.3 L. Plasma protein binding of seladelpar is greater than 99%.

Biotransformation

Seladelpar is primarily metabolized by CYP2C9 and to a lesser extent by CYP2C8 and CYP3A4. M2 is a major metabolite observed in human plasma, accounting for 17.6% of the total plasma radioactivity in the mass balance study and approximately doubling the plasma exposure compared to seladelpar. M2 is not expected to have clinically relevant pharmacological effects.

Elimination

In PBC patients, the apparent oral clearance of seladelpar is 12.6 L/h. Following administration of a single dose of 10 mg seladelpar in healthy subjects, mean elimination half-life was 6 hours for seladelpar. In PBC patients, the half-life range was 3.8 to 6.7 hours for seladelpar.

Following administration of an oral dose of radiolabelled seladelpar, 92.9% of radioactivity was recovered: 73.4% in urine and 19.5% in faeces. Urinary excretion of the dose as unchanged seladelpar was negligible (less than 0.01%).

Characteristics in specific groups or special populations

CYP2C9 genotype

Seladelpar is primarily metabolised in vitro by CYP2C9 which is a polymorphic enzyme. Seladelpar plasma exposure (dose-normalised AUC_0-inf) was 18% higher in CYP2C9 intermediate metabolisers (*1/*2, *1/*8, *1/*3, *2/*2, n=28) compared to CYP2C9 normal metabolisers (*1/*1, n=84) after a single dose of seladelpar 1 mg to 15 mg. No conclusion could be made for poor metabolisers due to only one identified subject with *2/*3 and no subjects with *3/*3 were identified

Age, weight, gender and race

Based on population pharmacokinetic analysis, age (19 to 79 years old), weight (45.8 to 127.5 kg), gender, and race (White, Black, Asian, other) do not have a clinically meaningful effect on the pharmacokinetics of seladelpar. No dose adjustments are warranted based on these factors.

Renal impairment

In a dedicated clinical study of patients with mild (eGFR ≥60 to <90 mL/min), moderate (eGFR ≥30 to <60 mL/min), and severe (<30 mL/min and not on dialysis) renal impairment, the AUC_0-inf of seladelpar was 48%, 33% and 3% greater than in patients with normal renal function, respectively, after administration of a single 10 mg dose of seladelpar. The C_max of seladelpar was similar in patients with renal impairment, compared to patients with normal renal function. These differences in seladelpar AUC_0-inf are not considered to be clinically meaningful. No dose adjustment of seladelpar is required for patients with mild, moderate, or severe renal impairment.

The pharmacokinetics of seladelpar have not been studied in patients requiring haemodialysis.

Hepatic impairment

Based on a clinical pharmacology study in subjects with mild, moderate, and severe hepatic impairment (Child-Pugh A, B, and C, respectively), seladelpar AUC was increased 1.10, 2.52, and 2.12-fold, and C_max was increased 1.33, 5.19, and 5.03-fold, respectively, compared to subjects with normal hepatic function.

In an additional study, seladelpar exposures (C_max, AUC) were 1.7 to 1.8-fold higher in PBC patients with mild hepatic impairment (Child-Pugh A) with portal hypertension and 1.6 to 1.9-fold higher in PBC patients with moderate hepatic impairment (Child-Pugh B), compared to PBC patients with mild hepatic impairment without portal hypertension, after a single oral dose of 10 mg seladelpar.

Following administration of 10 mg seladelpar once daily for 28 days in PBC patients with mild hepatic impairment (Child-Pugh A) with portal hypertension and PBC patients with moderate hepatic impairment (Child-Pugh B), there was no clinically meaningful accumulation of seladelpar (accumulation ratios were less than 1.2-fold).

Drug interaction studies

Effect of seladelpar on other medicinal products

Seladelpar has no clinically relevant effect on the pharmacokinetics of tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), simvastatin (CYP3A4 and OATP substrate), atorvastatin (CYP3A4 and OATP substrate), and rosuvastatin (BCRP and OATP substrate).

Effect of other medicinal products on seladelpar

P-gp inhibitor:

In a dedicated clinical drug interaction study, seladelpar exposures were not significantly altered when a single dose of 600 mg quinidine (a P-gp inhibitor) was co-administered in healthy subjects.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or toxicity to reproduction and development.

Reproductive and developmental toxicity

Seladelpar did not cause any foetal malformations or effects on embryo-foetal survival or growth in rats or rabbits. In rats, the exposure at NOAEL was 145-fold higher than the clinical AUC at the recommended dose of 10 mg, and 2-fold the clinical AUC in rabbits.

Oral administration of seladelpar at doses of 0, 5, 20 or 100 mg/kg/day in rats during gestation and lactation resulted in a dose-dependent reduction in pup body weights during the pre-weaning period at all dose levels, which was associated with slightly reduced pre-weaning survival at 100 mg/kg/day. Growth-related delays in developmental milestones were noted (eye opening and pinna unfolding at ≥5 mg/kg/day; hair growth and sexual maturity at 100 mg/kg/day). Growth reductions at 100 mg/kg/day continued into the post-weaning maturation period and were considered adverse. The exposure at the NOAEL of 20 mg/kg/day was 15-fold the clinical AUC.