Elafibranor (Monograph)

Brand name: Iqirvo
Drug class: Cholelitholytic Agents

Medically reviewed by Drugs.com on Dec 10, 2024. Written by ASHP.

Introduction

Peroxisome proliferator-activated receptor (PPAR) agonist.

Uses for Elafibranor

Primary Biliary Cholangitis

Treatment of primary biliary cholangitis (PBC) 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. Designated an orphan drug by FDA for treatment of primary biliary cholangitis.

Accelerated approval for this indication is based on the reduction of alkaline phosphatase. Continued approval may be contingent upon verification of clinical benefit (e.g., prevention of liver decompensation events, improvement of survival, etc.) 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 of primary biliary cholangitis. In patients who do not respond to UDCA or those with evidence of fibrosis progression, a second agent may be considered as add-on therapy. Treatment guidelines have not yet incorporated elafibranor and seladelpar into their recommendations.

Elafibranor Dosage and Administration

General

Pretreatment Screening

Evaluate patients for baseline muscle pain or myopathy.
Verify pregnancy status of females of reproductive potential.
Obtain baseline liver tests (alanine transaminase [ALT], aspartate transaminase [AST], total bilirubin, alkaline phosphatase).

Patient Monitoring

Monitor for new onset or worsening myalgia, myopathy, and/or rhabdomyolysis.
Given increased risk of fracture, bone health should be monitored per current standards of care.
Liver tests (i.e., ALT, AST, alkaline phosphatase, total bilirubin) should be obtained during treatment according to routine patient management. Patients should be closely monitored for disease progression and evidence of decompensation (e.g., ascites, variceal bleeding, hepatic encephalopathy), and consideration should be given for discontinuation of therapy if patients progress to moderate to severe hepatic impairment (Child-Pugh B or C).
Monitor for the development of biliary obstruction and interrupt treatment as indicated.

Administration

Administer orally without regard to meals.

In patients taking a bile acid sequestrant, administer elafibranor at least 4 hours before or after taking the bile acid sequestrant, or at as great an interval as possible.

Dosage

Adults

Primary Biliary Cholangitis

Oral

80 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.

Not recommended for use in patients with decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy).

Renal Impairment

Dosage adjustment not necessary.

Geriatric Patients

Routine dosage adjustment not necessary; however, consider closer monitoring of adverse events.

Cautions for Elafibranor

Contraindications

None

Warnings/Precautions

Myalgia, Myopathy, and Rhabdomyolysis

Cases of myalgia, myopathy, and rhabdomyolysis reported.

Evaluate patients prior to initiating elafibranor and periodically during therapy to assess for new or worsening muscle pain or injury.

Fractures

Fractures have occurred.

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

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on findings from animal studies.

Verify that females of reproductive potential are not pregnant prior to initiation of therapy. Advise females of reproductive potential to use effective non-hormonal contraceptives or add a barrier method when using hormonal contraceptives. Effective contraception should be utilized throughout treatment and continued for 3 weeks following the last dose of the drug.

Drug-induced Liver Injury

Drug-induced liver injury reported. In one patient, the clinical presentation was drug-induced autoimmune-like hepatitis (DI-ALH). Increases in transaminases (ALT and AST ≥5 times the ULN) and total bilirubin observed.

Obtain baseline liver tests (i.e., ALT, AST, alkaline phosphatase, total bilirubin) and complete clinical assessment prior to initiation of therapy. Continue to monitor during therapy according to routine patient management.

Interrupt treatment if liver tests worsen, or patient develops signs and symptoms consistent with clinical hepatitis (e.g., jaundice, right upper quadrant pain, eosinophilia). Consider permanent discontinuation if liver tests worsen after restarting the drug.

Hypersensitivity Reactions

Hypersensitivity reactions have occurred. Generally resolved after discontinuation of elafibranor and treatment with steroids and/or antihistamines.

If a severe hypersensitivity reaction occurs, permanently discontinue elafibranor. If a mild or moderate hypersensitivity reaction occurs, interrupt therapy and treat promptly. Monitor the patient until signs and symptoms resolve. If a hypersensitivity reaction recurs after elafibranor rechallenge, permanently discontinue therapy.

Biliary Obstruction

Avoid use of elafibranor in patients with complete biliary obstruction.

If biliary obstruction is suspected, interrupt therapy and treat patient as clinically indicated.

Specific Populations

Pregnancy

Based on data from animal studies, elafibranor may cause fetal harm when administered during pregnancy.

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

Report pregnancies in elafibranor-treated patients to Ipsen Pharmaceuticals Adverse Event reporting line at 1-855-463-5127 or [Web].

Lactation

Not known whether elafibranor is distributed into human milk. Effects of the drug on breast-fed infants or milk production also not known.

Because of the potential for serious adverse reactions, patients should not breastfeed during treatment and for 3 weeks following therapy.

Females and Males of Reproductive Potential

Because of risk of fetal harm, verify that females of reproductive potential are not pregnant prior to initiation of therapy.

Effective non-hormonal contraceptives or barrier methods when using hormonal contraceptives should be utilized during treatment with elafibranor and for at least 3 weeks after the last dose of the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No differences in efficacy observed between older patients and younger patients, and no dosage adjustments are recommended. However, older patients may be more sensitive to elafibranor, which may increase risk of adverse effects. Closer monitoring is recommended.

Hepatic Impairment

Not recommended for use in patients with decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy).

No clinically significant pharmacokinetic differences observed with elafibranor or its primary active metabolite in patients with mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C). However, systemic exposure of elafibranor and its primary active metabolite, GFT1007, increased by 2-fold and 2.6-fold, respectively, in patients with severe hepatic impairment (Child-Pugh C); therefore, elafibranor not recommended in patients with decompensated cirrhosis.

Renal Impairment

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

Common Adverse Effects

Most common adverse reactions (≥5%): weight gain, diarrhea, abdominal pain, nausea, vomiting, arthralgia, constipation, muscle injury, fracture, gastroesophageal reflux disease, dry mouth, weight loss, rash.

Drug Interactions

Metabolized by a cytosolic enzyme (PTGR1) to a major active metabolite, GFT1007; also metabolized by CYP2J2 and urine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A3, 1A4, and 2B7. GFT1007 is further metabolized by CYP2C8, UGT1A3, and UGT2B7.

Elafibranor and GFT1007 not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at the recommended dosage. Elafibranor and GFT1007 not expected to induce CYP1A2, CYP2B6, or CYP3A4 at the recommended dosage.

Elafibranor is not expected to inhibit UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B10, or 2B15 at the recommended dosage. GFT1007 is not expected to inhibit UGT1A1, 1A3, 1A4, 1A9, 2B7, 2B10, or 2B15. GFT1007 inhibited UGT1A6; however, clinical relevance unknown.

Elafibranor is an inhibitor of bile salt export pump (BSEP) and breast cancer resistance protein (BCRP); however, clinical significance unknown.

In vitro studies indicate that elafibranor is not expected to inhibit permeability-glycoprotein/multidrug resistance protein 1 (P-gp/MDR1), organic anion transporting polypeptides 1B1 (OATP1B1), organic cation transporter 1 (OCT1), OCT2, organic anion transporter 1 (OAT1), multidrug and toxin extrusion protein (MATE1), MATE2-K, and OAT3 and OATP1B3. GFT1007 is not expected to inhibit OAT3, OATP1B3, BSEP, P-gp/MDR1, BCRP, OATP1B1, OCT1, OCT2, OAT1, MATE1, and MATE2-K.

Elafibranor is a substrate for MRP2 and BCRP; however, clinical significance unknown. GFT1007 is not a substrate for MRP2 or BCRP. Elafibranor and GFT1007 are not substrates of P-gp, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.

Specific Drugs

Drug	Interaction	Comments
Bile Acid Sequestrants	May reduce the absorption and systemic exposure of elafibranor, thus reducing efficacy	Administer elafibranor at least 4 hours before or after taking a bile acid sequestrant, or at as great an interval as possible
HMG-CoA Reductase Inhibitors	Concomitant administration of elafibranor and HMG-CoA reductase inhibitors may increase risk of myopathy	Monitor for signs and symptoms of muscle injury in patients taking HMG-CoA reductase inhibitors with elafibranor; interrupt treatment if new onset or worsening muscle pain occurs
Hormonal Contraceptives	Elafibranor is a weak CYP3A4 inducer; concomitant administration of elafibranor and hormonal contraceptives containing progestin and ethinyl estradiol (CYP3A4 substrates) may lead to contraceptive failure and/or an increase in breakthrough bleeding	Patients should utilize non-hormonal contraceptives or add a barrier method to hormonal contraception during treatment with elafibranor and for at least 3 weeks after the last dose
Rifampin	Rifampin is an inducer of metabolizing enzymes; therefore, concomitant administration of rifampin and elafibranor may reduce the systemic exposure of elafibranor and its active metabolite, resulting in delayed or suboptimal biochemical response	Monitor biochemical response (e.g., reduction in alkaline phosphatase and total bilirubin) in patients taking rifampin with elafibranor

Elafibranor Pharmacokinetics

Absorption

Bioavailability

Median time to achieve peak plasma concentrations is 1.25 hours following oral administration.

Food

When administered with a high-fat, high-calorie meal, T_max of elafibranor and GFT1007 were delayed by 30 minutes and one hour, respectively, compared to fasted conditions.

Under fed conditions, peak plasma concentrations and AUC of elafibranor decreased by 50% and 15%, respectively, and peak plasma concentrations of GFT1007 decreased by 30%. AUC of GFT1007 was not affected.

Distribution

Plasma Protein Binding

>99%.

Elimination

Metabolism

Metabolized by 15-ketoprostaglandin 13-Δ reductase (PTGR1) to form its active metabolite, GFT1007. Inactive metabolite, GFT3351, is also formed. Further metabolized by CYP and UGT enzymes.

Elimination Route

Primarily excreted in the feces (77.1% total dose recovered; 56.7% as elafibranor and 6.08% as GFT1007). Approximately 19.3% was recovered in the urine, primarily as the inactive metabolite, GFT3351 (11.8%).

Half-life

Approximately 70 hours for elafibranor and 15 hours for GFT1007.

Stability

Storage

Oral

Tablets

Room temperature between 15–30°C, in original container.

Actions

Elafibranor and its main active metabolite, GFT1007, are peroxisome proliferator-activated receptor agonists. In vitro, PPAR-alpha, PPAR-gamma, and PPAR-delta are activated.
Mechanism of action not well understood, but may be related to inhibition of bile acid synthesis through PPAR-alpha and PPAR-delta 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 patients to read the FDA-approved patient labeling (Medication Guide).
Advise patients that elafibranor may cause rhabdomyolysis. Inform patients to report immediately to their healthcare provider any unexplained muscle symptoms such as pain, soreness, or weakness.
Inform patients or their caregiver(s) that elafibranor may increase the risk of bone fractures. Advise patients to call their healthcare provider to report any fractures.
Inform patients of the risk of elafibranor-induced liver injury. Instruct patients to report any signs or symptoms of liver injury (e.g., loss of appetite, nausea, increased fatigue, lower extremity edema, abdominal swelling, or jaundice/icterus) to their healthcare provider.
Advise patients to contact their healthcare provider or go to the emergency department if hypersensitivity reactions, such as rash, occur.
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 elafibranor treatment can be interrupted while the patient is being evaluated.
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 women that elafibranor may cause fetal harm; effective non-hormonal contraceptives, or barrier methods when using hormonal contraceptives, should be utilized during treatment with elafibranor and for at least 3 weeks after the last dose of the drug.
Advise women not to breastfeed during treatment with elafibranor and for 3 weeks after the last dose.
Inform patients of other important precautionary information.

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.