Seladelpar Lysine

Hepatic Impairment: Monitor patients with cirrhosis for evidence of decompensation. Consider discontinuation if patient progresses to moderate or severe hepatic impairment (Child-Pugh B or C). ( 8.7 )

8.1 Pregnancy Risk Summary There are insufficient data from human pregnancies exposed to LIVDELZI to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no malformations or effects on embryo-fetal survival occurred in pregnant rats or rabbits after seladelpar treatment at exposures of up to 176-times and 49-times the recommended dose based on AUC (area under the plasma concentration-time curve), respectively. Reduction of fetal growth associated with maternal toxicity occurred in pregnant rabbits at 49-times the recommended dose based on AUC, but not at 3-times the recommended dose. In a pre- and postnatal development study in rats with maternal dosing of seladelpar during organogenesis through lactation, postnatal growth and pre-weaning survival of offspring was reduced at 115-times the recommended dose based on AUC, but not at the lower exposure of 16-times the recommended dose (see Data ) . The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Report pregnancies to Gilead Sciences, Inc. at 1-800-445-3235. Data Animal Data No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 100 mg/kg/day seladelpar (176-times the recommended dose based on AUC) during the period of organogenesis. Oral administration of 40 mg/kg/day seladelpar in pregnant rabbits (49-times the recommended dose based on AUC) during organogenesis resulted in reduced fetal body weight, which was likely due to maternal toxicity (i.e., decreases in food consumption, body weight, and gravid uterine weight) and distended stomach. No treatment-related fetal malformations or effects on embryo-fetal survival occurred in rabbits at 49-times the recommended dose. No adverse effects on embryo-fetal development were observed at 10 mg/kg/day (3-times the recommended dose based on AUC). A pre- and postnatal development study was performed using oral administration of seladelpar at doses of 0 (vehicle), 5, 20, or 100 mg/kg/day in pregnant rats during organogenesis through lactation. Treatment with 5 mg/kg/day or higher (4-times the recommended dose based on AUC) resulted in a dose-dependent reduction in pup body weight during the pre-weaning period. The weight reduction in offspring was associated with delays in developmental milestones (i.e., eye opening and pinna unfolding at 5 mg/kg/day and higher; hair growth and sexual maturity at 100 mg/kg/day). Reduction in pup body weight at 100 mg/kg/day (115-times the recommended dose based on AUC), which continued into the post-weaning maturation period, was associated with a slight decrease in pre-weaning survival and was considered adverse. No adverse effects were found in clinical observations, neurobehavioral assessment, or reproductive performance testing in the offspring of females treated with seladelpar. At 20 mg/kg/day (16-times the recommended dose based on AUC), none of the observed effects in offspring were considered to be adverse.

8.2 Lactation Risk Summary There are no data on the presence of seladelpar or its metabolite in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LIVDELZI and any potential adverse effects on the breastfed infant from LIVDELZI or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of LIVDELZI in pediatric patients have not been established.

8.5 Geriatric Use Of the 128 LIVDELZI-treated patients in Trial 1, 29 (23%) patients were 65 years of age and older and 2 (2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 to 75 years of age and younger adult patients. No dosage adjustment for patients 65 years of age and older is necessary. Clinical studies of LIVDELZI did not include sufficient numbers of patients 75 years of age and older to determine whether they respond differently from younger adult patients. Because of limited clinical experience with LIVDELZI in patients older than 75 years old, closer monitoring of adverse events in patients older than 75 years is recommended [see Clinical Pharmacology (12.3) ] .

8.6 Renal Impairment The recommended dosage in patients with mild, moderate, or severe renal impairment is the same as in patients with normal renal function. Patients with end-stage renal disease on dialysis have not been studied [see Clinical Pharmacology (12.3) ] .

8.7 Hepatic Impairment No dosage adjustment is recommended for PBC patients with mild hepatic impairment (Child-Pugh A) [see Clinical Pharmacology (12.3) ] . The safety and efficacy of LIVDELZI in patients with decompensated cirrhosis have not been established. Use of LIVDELZI is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy). Monitor patients with cirrhosis for evidence of decompensation. Consider discontinuing LIVDELZI if the patient progresses to moderate or severe hepatic impairment (Child-Pugh B or C).

8.8 CYP2C9 Poor Metabolizers Monitor CYP2C9 poor metabolizers who receive a concomitant moderate to strong CYP3A4 inhibitor more frequently for adverse reactions. Seladelpar is a CYP2C9 and CYP3A4 substrate. Increased seladelpar AUC is expected in patients who are CYP2C9 poor metabolizers with concomitant use of a moderate to strong CYP3A4 inhibitor [see Drug Interactions (7.1) , Clinical Pharmacology (12.5) ] .

12.1 Mechanism of Action Seladelpar is a peroxisome proliferator-activated receptor (PPAR)-delta (δ) agonist. However, the mechanism by which seladelpar exerts its therapeutic effects in patients with PBC is not well understood. Pharmacological activity that is potentially relevant to therapeutic effects includes inhibition of bile acid synthesis through activation of PPARδ, which is a nuclear receptor expressed in most tissues, including the liver. Published studies show that PPARδ activation by seladelpar reduces bile acid synthesis through Fibroblast Growth Factor 21 (FGF21)-dependent downregulation of CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol.

12.2 Pharmacodynamics Pharmacodynamic Markers In patients with PBC treated with 10 mg once daily of LIVDELZI (Trial 1), a greater reduction in mean ALP from baseline was observed as early as 1 month after treatment compared to the placebo group and lower ALP was generally maintained through month 12 [see Clinical Studies (14) ] . In another study in which patients with PBC were treated with 2, 5, or 10 mg once daily of seladelpar, a dose dependent reduction in mean ALP was observed. Cardiac Electrophysiology At 20-times the recommended dose of 10 mg, LIVDELZI did not cause clinically significant QTc interval prolongation.

12.3 Pharmacokinetics Following a single dose administration, seladelpar systemic exposure increased dose-proportionally from 2 mg (0.2 times the recommended dosage) to 15 mg (1.5 times the recommended dosage) and greater than dose proportionally at higher doses. For a dose increase from 10 mg to 200 mg (20 times the recommended dosage), mean C max and mean AUC for seladelpar increased 70-fold and 27-fold, respectively. Following once daily dosing, seladelpar steady-state was achieved by day 4 and AUC increase was less than 30%. In PBC patients, median (CV) C max and AUC for seladelpar was 90.5 (42.5%) ng/mL and 817 (44%) ng*h/mL, respectively at steady state following once daily dosing of 10 mg. Absorption The median time to peak concentration (T max ) was 1.5 hours for seladelpar. Effect of Food No clinically significant differences in seladelpar pharmacokinetics were observed following administration of a high-fat meal in healthy subjects. Distribution Seladelpar steady state apparent volume of distribution was approximately 110.3 L. Seladelpar plasma protein binding is greater than 99%. Elimination 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. Metabolism Seladelpar is primarily metabolized in vitro by CYP2C9 and to a lesser extent by CYP2C8 and CYP3A4, resulting in the three major metabolites: seladelpar sulfoxide (M1), desethyl-seladelpar (M2), and desethyl-seladelpar sulfoxide (M3). The metabolite-to-parent AUC ratios were 0.36, 2.32 and 0.63 for M1, M2 and M3, respectively. Median T max for metabolites were 10 hours for M1 and 4 hours for M2 and M3. None of the major metabolites have pharmacological activity. Excretion Seladelpar is primarily eliminated in urine as metabolites. Following a single oral dose of 10 mg radiolabeled seladelpar in humans, approximately 73.4% of the dose was recovered in urine (less than 0.01% unchanged) and 19.5% in feces (2.02% unchanged) within 216 hours. Biliary excretion of seladelpar was suggested by an animal study. Specific Populations No clinically significant differences in the pharmacokinetics of seladelpar were observed based on age (19 to 79 years old), body mass index (BMI) (17.6 to 45.0 kg/m 2 ), weight (45.8 to 127.5 kg), sex, and race (White, Black, or other). Patients with Renal Impairment In subjects with mild (eGFR ≥60 to <90 mL/min/1.73 m 2 , MDRD), moderate (eGFR ≥30 to <60 mL/min/1.73 m 2 ), and severe (<30 mL/min/1.73 m 2 and not on dialysis) renal impairment, the AUC inf of seladelpar was 10% higher, 54% higher, and similar to that in subjects with normal renal function, respectively, after administration of a single 10 mg dose of seladelpar. The difference in C max of seladelpar was less than 18% in subjects with renal impairment compared to subjects with normal renal function [see Use in Specific Populations (8.6) ] . The pharmacokinetics of seladelpar have not been studied in patients requiring hemodialysis. Patients with Hepatic Impairment Hepatic Impairment of various etiologies: Following a single oral dose of 10 mg seladelpar, seladelpar AUC increased 1.1-fold in subjects with mild (Child-Pugh A), 2.5-fold in moderate (Child-Pugh B), and 2.1-fold in severe (Child-Pugh C) hepatic impairment. Seladelpar C max increased 1.3-fold in subjects with mild (Child-Pugh A), 5.2-fold in moderate (Child-Pugh B), and 5-fold in severe (Child-Pugh C) hepatic impairment. Hepatic Impairment in patients with PBC: Compared to PBC patients with mild hepatic impairment (Child-Pugh A) without portal hypertension, seladelpar exposures (C max , AUC) were 1.7 to 1.8-fold higher in PBC patients with mild hepatic impairment with portal hypertension, 1.6 to 1.9-fold higher in PBC patients with moderate hepatic impairment (Child-Pugh B), and 2.1 to 2.5-fold higher in PBC patients with severe hepatic impairment (Child-Pugh C) after a single oral dose of 10 mg seladelpar. Accumulation ratios were less than 1.2-fold in PBC patients with mild hepatic impairment with portal hypertension and PBC patients with moderate hepatic impairment following 10 mg seladelpar once daily dosing for 28 days. Drug Interaction Studies Effect of Other Drugs on Seladelpar Carbamazepine Seladelpar AUC 0–inf decreased by approximately 44% and C max by 24% following administration of a single 10 mg seladelpar dose after carbamazepine 300 mg twice daily for 8 days in healthy subjects. The carbamazepine (CYP3A and CYP2C9 inducer) dose was escalated from 100 mg twice daily for 3 days followed by 200 mg twice daily for 4 days to 300 mg twice daily. Fluconazole Seladelpar AUC 0–inf increased by 2.4-fold and C max by 1.4-fold following concomitant use of a single 10 mg seladelpar dose with 400 mg fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) in healthy subjects. Cyclosporine Seladelpar AUC 0–inf increased by 2.1-fold and C max by 2.9-fold following concomitant use of a single 10 mg seladelpar dose with 600 mg cyclosporine (OATP1B1, OATP1B3, and BCRP inhibitor) in healthy subjects. Probenecid Seladelpar AUC 0–inf increased by 2-fold and C max by 4.69-fold following concomitant use of a single 10 mg seladelpar dose with 500 mg probenecid in healthy subjects . Quinidine Seladelpar exposures were not significantly altered when a single dose of 600 mg quinidine (P-gp inhibitor) was coadministered in healthy subjects. Other Drugs: No clinically significant differences in seladelpar pharmacokinetics were predicted when used concomitantly with strong CYP3A4 inhibitors or CYP2C8 inhibitors. In Vitro Studies Seladelpar is a substrate of CYP2C9, CYP2C8, CYP3A4, and the transporters BCRP, P-gp, OATP1B1, OATP1B3, and OAT3. Seladelpar is not a substrate of MATE1, MATE2-K, OAT1, OCT1, or OCT2 transporters. Effects of Seladelpar on other drugs In clinical studies, no clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with seladelpar: tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), simvastatin (CYP3A4 and OATP substrate), atorvastatin (CYP3A4 and OATP substrate), or rosuvastatin (BCRP and OATP substrate). In Vitro Studies Based on in vitro studies, 10 mg seladelpar does not significantly affect the pharmacokinetics of concomitant drugs that are substrates of CYP enzymes (1A2, 2B6, 2C8, 2C19, 2D6, 3A4), UGTs, P-gp, MATEs, OCT1, OCT2, OAT1, or OAT3.

12.5 Pharmacogenomics CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3. Compared to CYP2C9 normal metabolizers (*1/*1, n=84) after a single dose of seladelpar 1 mg to 15 mg, dose-normalized AUC 0–inf was 48% higher in CYP2C9 poor metabolizers (*2/*3, n=2) and 24% higher in CYP2C9 intermediate metabolizers (*1/*2, *1/*8, *1/*3, *2/*2, n=28). Dose-normalized C max was similar for CYP2C9 normal, intermediate, and poor metabolizers. Seladelpar pharmacokinetics was not evaluated in patients who are CYP2C9 poor metabolizers with two no function alleles (e.g., *3/*3). CYP2C9 poor metabolizers may have increased AUC when seladelpar is used concomitantly with a moderate to strong CYP3A4 inhibitor [see Drug Interactions (7.1) , Use in Specific Populations (8.8) ] . The prevalence of CYP2C9 poor metabolizers is approximately 2 to 3% in White populations, 0.5 to 4% in Asian populations, and <1% in African American populations. Additional decreased or nonfunctional alleles (e.g., *5, *6, *11) are more prevalent in African American populations.

Following a single dose administration, seladelpar systemic exposure increased dose-proportionally from 2 mg (0.2 times the recommended dosage) to 15 mg (1.5 times the recommended dosage) and greater than dose proportionally at higher doses. For a dose increase from 10 mg to 200 mg (20 times the recommended dosage), mean C max and mean AUC for seladelpar increased 70-fold and 27-fold, respectively. Following once daily dosing, seladelpar steady-state was achieved by day 4 and AUC increase was less than 30%. In PBC patients, median (CV) C max and AUC for seladelpar was 90.5 (42.5%) ng/mL and 817 (44%) ng*h/mL, respectively at steady state following once daily dosing of 10 mg. Absorption The median time to peak concentration (T max ) was 1.5 hours for seladelpar. Effect of Food No clinically significant differences in seladelpar pharmacokinetics were observed following administration of a high-fat meal in healthy subjects. Distribution Seladelpar steady state apparent volume of distribution was approximately 110.3 L. Seladelpar plasma protein binding is greater than 99%. Elimination 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. Metabolism Seladelpar is primarily metabolized in vitro by CYP2C9 and to a lesser extent by CYP2C8 and CYP3A4, resulting in the three major metabolites: seladelpar sulfoxide (M1), desethyl-seladelpar (M2), and desethyl-seladelpar sulfoxide (M3). The metabolite-to-parent AUC ratios were 0.36, 2.32 and 0.63 for M1, M2 and M3, respectively. Median T max for metabolites were 10 hours for M1 and 4 hours for M2 and M3. None of the major metabolites have pharmacological activity. Excretion Seladelpar is primarily eliminated in urine as metabolites. Following a single oral dose of 10 mg radiolabeled seladelpar in humans, approximately 73.4% of the dose was recovered in urine (less than 0.01% unchanged) and 19.5% in feces (2.02% unchanged) within 216 hours. Biliary excretion of seladelpar was suggested by an animal study. Specific Populations No clinically significant differences in the pharmacokinetics of seladelpar were observed based on age (19 to 79 years old), body mass index (BMI) (17.6 to 45.0 kg/m 2 ), weight (45.8 to 127.5 kg), sex, and race (White, Black, or other). Patients with Renal Impairment In subjects with mild (eGFR ≥60 to <90 mL/min/1.73 m 2 , MDRD), moderate (eGFR ≥30 to <60 mL/min/1.73 m 2 ), and severe (<30 mL/min/1.73 m 2 and not on dialysis) renal impairment, the AUC inf of seladelpar was 10% higher, 54% higher, and similar to that in subjects with normal renal function, respectively, after administration of a single 10 mg dose of seladelpar. The difference in C max of seladelpar was less than 18% in subjects with renal impairment compared to subjects with normal renal function [see Use in Specific Populations (8.6) ] . The pharmacokinetics of seladelpar have not been studied in patients requiring hemodialysis. Patients with Hepatic Impairment Hepatic Impairment of various etiologies: Following a single oral dose of 10 mg seladelpar, seladelpar AUC increased 1.1-fold in subjects with mild (Child-Pugh A), 2.5-fold in moderate (Child-Pugh B), and 2.1-fold in severe (Child-Pugh C) hepatic impairment. Seladelpar C max increased 1.3-fold in subjects with mild (Child-Pugh A), 5.2-fold in moderate (Child-Pugh B), and 5-fold in severe (Child-Pugh C) hepatic impairment. Hepatic Impairment in patients with PBC: Compared to PBC patients with mild hepatic impairment (Child-Pugh A) without portal hypertension, seladelpar exposures (C max , AUC) were 1.7 to 1.8-fold higher in PBC patients with mild hepatic impairment with portal hypertension, 1.6 to 1.9-fold higher in PBC patients with moderate hepatic impairment (Child-Pugh B), and 2.1 to 2.5-fold higher in PBC patients with severe hepatic impairment (Child-Pugh C) after a single oral dose of 10 mg seladelpar. Accumulation ratios were less than 1.2-fold in PBC patients with mild hepatic impairment with portal hypertension and PBC patients with moderate hepatic impairment following 10 mg seladelpar once daily dosing for 28 days. Drug Interaction Studies Effect of Other Drugs on Seladelpar Carbamazepine Seladelpar AUC 0–inf decreased by approximately 44% and C max by 24% following administration of a single 10 mg seladelpar dose after carbamazepine 300 mg twice daily for 8 days in healthy subjects. The carbamazepine (CYP3A and CYP2C9 inducer) dose was escalated from 100 mg twice daily for 3 days followed by 200 mg twice daily for 4 days to 300 mg twice daily. Fluconazole Seladelpar AUC 0–inf increased by 2.4-fold and C max by 1.4-fold following concomitant use of a single 10 mg seladelpar dose with 400 mg fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) in healthy subjects. Cyclosporine Seladelpar AUC 0–inf increased by 2.1-fold and C max by 2.9-fold following concomitant use of a single 10 mg seladelpar dose with 600 mg cyclosporine (OATP1B1, OATP1B3, and BCRP inhibitor) in healthy subjects. Probenecid Seladelpar AUC 0–inf increased by 2-fold and C max by 4.69-fold following concomitant use of a single 10 mg seladelpar dose with 500 mg probenecid in healthy subjects . Quinidine Seladelpar exposures were not significantly altered when a single dose of 600 mg quinidine (P-gp inhibitor) was coadministered in healthy subjects. Other Drugs: No clinically significant differences in seladelpar pharmacokinetics were predicted when used concomitantly with strong CYP3A4 inhibitors or CYP2C8 inhibitors. In Vitro Studies Seladelpar is a substrate of CYP2C9, CYP2C8, CYP3A4, and the transporters BCRP, P-gp, OATP1B1, OATP1B3, and OAT3. Seladelpar is not a substrate of MATE1, MATE2-K, OAT1, OCT1, or OCT2 transporters. Effects of Seladelpar on other drugs In clinical studies, no clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with seladelpar: tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), simvastatin (CYP3A4 and OATP substrate), atorvastatin (CYP3A4 and OATP substrate), or rosuvastatin (BCRP and OATP substrate). In Vitro Studies Based on in vitro studies, 10 mg seladelpar does not significantly affect the pharmacokinetics of concomitant drugs that are substrates of CYP enzymes (1A2, 2B6, 2C8, 2C19, 2D6, 3A4), UGTs, P-gp, MATEs, OCT1, OCT2, OAT1, or OAT3.