Brand name: Livdelzi
Drug class: Cholelitholytic Agents

Introduction

Peroxisome proliferator-activated receptor (PPAR)-delta (δ) agonist.

Uses for Seladelpar

Primary Biliary Cholangitis

Treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in adults who have had an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. Seladelpar has been designated an orphan drug by FDA for treatment of primary biliary cholangitis.

Accelerated approval of seladelpar for this indication is based on the reduction of alkaline phosphatase (ALP). Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval may be contingent upon verification of clinical benefit (e.g., prevention of liver decompensation events, improvement of survival) in confirmatory studies.

Not recommended for use in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy).

Several FDA-approved drugs are currently available for treatment of primary biliary cholangitis (UDCA, obeticholic acid, elafibranor, seladelpar). The American College of Gastroenterology, Chronic Liver Disease Foundation, and American Association for the Study of Liver Diseases recommend UDCA as first-line treatment for primary biliary cholangitis. In patients who do not respond to UDCA, (i.e., patients with persistently elevated ALP or lack of normalization of total bilirubin after 12 months of therapy with UDCA), those considered high risk via predictive models (e.g., UK-PBC, GLOBE, PBC), or those with evidence of fibrosis progression, a second agent may be considered as add-on therapy. Treatment guidelines have not yet incorporated seladelpar and elafibranor into their recommendations.

Seladelpar Dosage and Administration

General

Pretreatment Screening

• Obtain baseline liver tests (i.e., ALT, AST, ALP, total bilirubin).

• Screen patients for complete biliary obstruction and avoid treatment with seladelpar if identified.

Patient Monitoring

• Given increased risk of fracture, monitor bone health per current standards of care.

• Obtain liver tests (i.e., ALT, AST, ALP, total bilirubin) at initiation and during treatment according to routine patient management. Closely monitor patients for disease progression and evidence of decompensation (e.g., ascites, variceal bleeding, hepatic encephalopathy).

• Monitor for the development of biliary obstruction and interrupt treatment as indicated.

Administration

Administer orally without regard to meals.

Administer seladelpar at least 4 hours before or 4 hours after taking a bile acid sequestrant.

Dosage

Available as seladelpar lysine; dosage expressed in terms of seladelpar.

Adults

Primary Biliary Cholangitis

Oral

10 mg once daily either in combination with UDCA or as monotherapy (for those intolerant of UDCA).

Special Populations

Hepatic Impairment

Mild (Child-Pugh A): Dosage adjustment not necessary.

Moderate to severe (Child-Pugh B or C): Use not recommended.

Renal Impairment

Dosage adjustment not necessary.

Geriatric Patients

Dosage adjustment not necessary.

Cautions for Seladelpar

Contraindications

• None.

Warnings/Precautions

Fractures

Fractures have occurred.

Consider risk of fracture and monitor bone health according to current standards of care.

Liver Test Abnormalities

Dose-related increases in AST and ALT, ≥ 3-times the ULN, associated with patients receiving 5- and 20-times the recommended dosage. Increases in AST and ALT not observed at the recommended dosage of 10 mg once daily.

Obtain baseline liver tests (i.e., ALT, AST, ALP, total bilirubin) prior to initiating seladelpar. Monitor during treatment according to routine patient management. Interrupt treatment if liver function tests worsen, or if the patient develops signs and symptoms consistent with clinical hepatitis (e.g., jaundice, right upper quadrant pain, eosinophilia). If treatment is restarted following interruption and liver function tests worsen, consider permanent discontinuation.

Biliary Obstruction

Avoid use in patients with complete biliary obstruction.

Assess patients for complete biliary obstruction prior to initiation of therapy. If biliary obstruction is suspected, interrupt therapy and treat patient as clinically indicated.

Specific Populations

Pregnancy

Human data regarding seladelpar use during pregnancy are inadequate to inform a drug-associated risk.

Report pregnancies in seladelpar-treated patients to Gilead Sciences at 1-800-445-3235.

Lactation

Not known whether seladelpar is distributed into human milk. Effects of the drug on breastfed infants or milk production also not known.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No differences in safety or efficacy observed between geriatric patients ≥65 years of age and younger patients. Due to limited clinical experience in patients ≥75 years of age, close monitoring is recommended.

Hepatic Impairment

Not recommended for use in patients with decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy). Peak plasma concentrations increased 5-fold in patients with severe (Child-Pugh C) hepatic impairment.

Monitor patients with cirrhosis for evidence of decompensation; discontinue therapy if progression to moderate or severe hepatic impairment (Child-Pugh B or C) occurs.

Renal Impairment

No differences in safety or efficacy observed between patients with renal impairment and patients with normal renal function; no dosage adjustments recommended.

Safety and efficacy not evaluated in patients with end-stage renal disease on dialysis.

Pharmacogenomic Considerations

Seladelpar is a CYP2C9 and CYP3A4 substrate. In patients who are CYP2C9 poor metabolizers (i.e., CYP2C9*2, CYP2C9*3), increased seladelpar AUC is expected.

Common Adverse Effects

Most common adverse reactions (≥5%): headache, abdominal pain, nausea, abdominal distension, dizziness.

Drug Interactions

Metabolized by CYP2C9, and to a lesser extent, by CYP2C8 and CYP3A4.

In vitro studies indicate that seladelpar and its metabolites do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, or CYP3A4. Seladelpar did not induce CYP1A2, CYP2B6, or CYP2C8.

In vitro studies indicate that seladelpar and its metabolites do not inhibit UDP-glucuronosyltransferases (UGTs).

Substrate of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), and organic anion transporter (OAT) 3; not a substrate of multidrug and toxin extrusion (MATE) 1, MATE2-K, OAT1, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, or OCT2 transporters.

In vitro studies indicate that seladelpar and its metabolites do not inhibit P-gp, MATE1, MATE2-K, OCT1, OCT2, OAT1, or OAT3.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP2C9 Inhibitors: Seladelpar is a CYP2C9 substrate. Concomitant administration of seladelpar with strong CYP2C9 inhibitors is predicted to increase seladelpar exposure by 3.7-fold and should be avoided.

Dual Moderate CYP2C9 and Moderate to Strong CYP3A4 Inhibitors: Seladelpar is a substrate of CYP2C9 and CYP3A4. Concomitant administration of seladelpar with drugs that are moderate inhibitors of CYP2C9 and moderate-to-strong inhibitors of CYP3A4 may increase seladelpar exposure. Monitor closely for adverse effects.

Strong CYP3A4 Inhibitors in CYP2C9 Poor Metabolizers:Concomitant administration of seladelpar with drugs that are moderate-to-strong CYP3A4 inhibitors in CYP2C9 poor metabolizers (i.e., CYP2C9*2, CYP2C9*3) may increase seladelpar exposure. Monitor closely for adverse effects.

CYP2C9 substrates:No clinically significant differences in pharmacokinetics of a CYP2C9 substrate observed.

CYP3A4 substrates: No clinically significant differences in pharmacokinetics of CYP3A4 substrates observed.

Drugs Affecting Transport Systems

OAT3 Inhibitors: Seladelpar is an OAT3 substrate. Concomitant administration of seladelpar with OAT3 inhibitors can increase seladelpar exposure and should be avoided.

BCRP Inhibitors: Seladelpar is a BCRP substrate. Concomitant administration of seladelpar with a BCRP inhibitor may increase seladelpar exposure. Monitor patients closely for adverse effects.

Specific Drugs

Seladelpar Pharmacokinetics

Absorption

Onset

1.5 hours; steady state achieved by day 4.

Food

No clinically significant differences observed following administration of a high-fat meal.

Distribution

Plasma Protein Binding

>99%.

Elimination

Metabolism

Metabolized by CYP2C9, and to a lesser extent, CYP2C8 and CYP3A4 to 3 inactive metabolites (M1, M2, M3).

Elimination Route

Primarily excreted in the urine (73%) and to a lesser extent in the feces (20%).

Half-life

6 hours in healthy patients; 3.8 to 6.7 hours in patients with primary biliary cholangitis.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted between 15–30°C).

Actions

• Peroxisome proliferator-activated receptor-δ agonist.

• Mechanism of action not well understood, but may be related to inhibition of bile acid synthesis through PPAR-δ activation and Fibroblast Growth Factor 21 (FGF-21)-dependent downregulation of the enzyme responsible for the synthesis of bile acids from cholesterol, CYP7A1.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Inform patients that seladelpar may increase the risk of bone fractures. Advise patients to call their healthcare provider to report any fractures.

• Instruct patients to report any signs or symptoms of liver-related adverse reactions (e.g., loss of appetite, nausea, increased fatigue, lower extremity edema, abdominal swelling, or jaundice/icterus) to their healthcare provider.

• Instruct patients to immediately report any signs or symptoms of biliary obstruction (e.g., right upper quadrant pain, jaundice) to their healthcare provider so that seladelpar treatment can be interrupted while the patient is being evaluated.

• Advise patients that there is a pregnancy safety study that captures pregnancy outcomes in women exposed to seladelpar during pregnancy, and to report pregnancies and pregnancy outcomes by calling 1-800-445-3235.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Seladelpar is obtained through designated specialty pharmacies. Contact manufacturer or consult the seladelpar website ([Web]) for specific availability information.

Reload page with references included

Related/similar drugs

Medical Disclaimer