Pexidartinib (Monograph)

Brand name: Turalio
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical name: 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine
Molecular formula: C₂₀H₁₅ClF₃N₅
CAS number: 1029044-16-3

Medically reviewed by Drugs.com on Jun 23, 2022. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases including colony stimulating factor 1 receptor (CSF-1R), c-Kit proto-oncogene proteins (c-Kit), and fms-like tyrosine kinase-3 (Flt-3).

Uses for Pexidartinib

Tenosynovial Giant Cell Tumor

For the treatment of adult patients with symptomatic tenosynovial giant cell tumor (also referred to as giant cell tumor of the tendon sheath [GCT-TS] or pigmented villonodular synovitis [PVNS]) associated with severe morbidity or functional limitations that is not amenable to improvement with surgery.

Designated an orphan drug by FDA for the treatment of this condition.

Pexidartinib Dosage and Administration

General

Pretreatment Screening

• Obtain liver function tests (i.e., AST, ALT, total bilirubin, direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase [GGT]) prior to initiating pexidartinib. Do not initiate pexidartinib in patients with preexisting elevations in AST, ALT, alkaline phosphatase, active liver or biliary tract disease, or total or direct bilirubin greater than the upper limit of normal (ULN).

• Verify pregnancy status in females of reproductive potential prior to the initiation of pexidartinib.

Patient Monitoring

• Monitor liver function tests weekly during the first 8 weeks of therapy, every 2 weeks for the next month, and then every 3 months thereafter.

REMS

• Because pexidartinib may cause serious and potentially fatal liver injury, the drug is only available through a restricted program under a REMS.

• Contact the manufacturer or visit [Web] for additional information.

Administration

Oral Administration

Administer orally on an empty stomach (at least 1 hour before or 2 hours after a meal or snack).

Swallow pexidartinib capsules whole; do not open, break, or chew the capsules.

If a dose of pexidartinib is missed or vomited, take the prescribed dose at the next scheduled time; do not take an additional dose to replace the missed dose.

Dosage

Dosage of pexidartinib hydrochloride is expressed in terms of pexidartinib.

Adults

Tenosynovial Giant Cell Tumor

Oral

400 mg orally twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

If adverse reactions occur during pexidartinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary. If dosage reduction is required, the dosage of pexidartinib should be reduced as described in Table 1.

The following Dosage Modification for Pexidartinib Toxicity table indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for certain adverse effects according to severity.

Confirm alkaline phosphatase elevations as liver isoenzyme fraction.

Concomitant Use with Moderate or Strong CYP3A Inhibitors or UGT Inhibitors

Oral

Avoid concomitant use of pexidartinib and moderate or strong CYP3A inhibitors or UGT inhibitors. If concomitant use cannot be avoided, reduce the dosage of pexidartinib as described in Table 3. If the moderate or strong CYP3A inhibitor or UGT inhibitors is discontinued, return the pexidartinib dosage (after 3 elimination half-lives of the CYP3A or UGT inhibitor) to the dosage used prior to initiation of the CYP3A or UGT inhibitor.

Special Populations

Hepatic Impairment

Moderate hepatic impairment (total bilirubin >1.5 and up to 3 times ULN, not due to Gilbert syndrome, with any AST concentration): Reduce dosage to 200 mg twice daily.

Severe hepatic impairment (total bilirubin 3–10 times the ULN with any AST concentration): Pharmacokinetics not studied.

Renal Impairment

Mild to severe renal impairment (Cl_cr 15–89 mL/minute): Reduce dosage to 200 mg in the morning and 400 mg in the evening.

Geriatric Patients

Manufacturer makes no specific dosage recommendations for geriatric patients.

Related/similar drugs

Turalio

Cautions for Pexidartinib

Contraindications

• None.

Warnings/Precautions

Warnings

Hepatotoxicity

A boxed warning regarding the risk of serious and potentially fatal liver injury is included in the prescribing information for pexidartinib. Hepatotoxicity with ductopenia and cholestasis has been reported. Unknown whether liver injury occurs in the absence of elevated serum aminotransferase concentrations.

Because of this risk, pexidartinib is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Requirements of the REMS program may be accessed at [Web] or calling 833-887-2546.

Avoid pexidartinib in patients with preexisting elevated AST or ALT concentrations; total bilirubin or direct bilirubin greater than ULN; or active liver or biliary tract disease, including increased alkaline phosphatase. Administration of pexidartinib with a high-fat meal increases exposure to the drug by 100% and may increase the risk of hepatotoxicity.

Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase (GGT) prior to initiation of pexidartinib, weekly for the first 8 weeks, every 2 weeks for the next month, and then every 3 months thereafter. Based on the severity of hepatotoxicity, temporary interruption of therapy, dosage reduction, or permanent discontinuance of the drug may be necessary.

Recurrence of elevated serum aminotransferases, bilirubin, or alkaline phosphatase may occur following resumption of pexidartinib therapy at a reduced dosage. Monitor liver function tests weekly for the initial month after rechallenge.

Other Warnings and Precautions

Fetal/Neonatal Morbidity and Mortality

Based on animal data and its mechanism of action, pexidartinib may cause fetal harm.

Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Apprise pregnant females of potential risk to a fetus. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with pexidartinib and for 1 month after discontinuing treatment; nonhormonal contraceptives should be used because concomitant use of pexidartinib and hormonal contraceptives may result in decreased systemic exposure to the hormonal contraceptive and reduced efficacy of the hormonal contraceptive.

Males with female partners of reproductive potential should also use effective contraception during treatment with pexidartinib and for 1 week after discontinuing treatment.

Specific Populations

Pregnancy

May cause fetal harm based on animal data and its mechanism of action.

Available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of pexidartinib.

Lactation

Not known whether pexidartinib or its metabolites are distributed into human milk. Effects of the drug on breast-fed infants or on the production of milk are also unknown.

Females should not breast-feed while receiving the drug and for at least one week after the last dose.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to the initiation of pexidartinib.

Advise females of reproductive potential to use effective nonhormonal contraception during treatment with pexidartinib and for 1 month after the final dose.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with pexidartinib and for at least 1 week after the final dose.

May impair male and female fertility based on animal studies.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Experience in patients ≥65 years of age is insufficient to determine whether geriatric patients respond differently than younger individuals.

Hepatic Impairment

Mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] with AST greater than ULN or total bilirubin >1 up to 1.5 times ULN with any AST concentration): No clinically significant effect on pharmacokinetics of pexidartinib; no dosage adjustment necessary.

Moderate hepatic impairment (total bilirubin >1.5 and up to 3 times ULN, not due to Gilbert syndrome, with any AST concentration): AUC of pexidartinib increased by 43% compared to patients with normal hepatic function; reduce dosage of pexidartinib to 200 mg twice daily.

Severe (total bilirubin greater than 3–10 times ULN and any AST concentration) hepatic impairment: Not studied.

Renal Impairment

Mild to severe renal impairment (Cl_cr 15–89 mL/minute): AUC of pexidartinib increased by approximately 30% compared to patients with normal renal function; reduce dosage of pexidartinib to 200 mg in the morning and 400 mg in the evening.

Race and Gender

No clinically significant effect on pharmacokinetics of pexidartinib.

Common Adverse Effects

Adverse effects occurring in >20% of patients: Increased lactate dehydrogenase concentrations, increased AST/ALT concentrations, hair color changes, fatigue, decreased neutrophils, increased cholesterol, increased alkaline phosphatase concentrations, decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia, decreased phosphate.

Drug Interactions

Primarily metabolized by CYP3A4 and glucuronidation by uridine diphosphate-glucuronosyltransferase to the major inactive N-glucuronide metabolite. In vitro, likely to inhibit CYP2B6 and induce CYP2B6 at clinically relevant concentrations.

At clinically relevant concentrations, likely to inhibit UGT1A1. Inhibitor of multidrug and toxin extrusion (MATE) 1, MATE2-K, organic anion transporter protein (OATP) 1B1, OATP1B3 and OATP2B1. In vitro, not a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), OAT1, OAT3, organic cation transporter (OCT) 1, OCT2, OATP1B1, OATP1B3, OATP2B1, or bile salt export pump (BSEP).

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Moderate or Strong CYP3A Inhibitors: Concomitant use may increase concentrations of pexidartinib and increase risk and severity of adverse reactions. Avoid concomitant use, including grapefruit and grapefruit products. If concomitant use cannot be avoided, reduce dosage of pexidartinib as described in Table 4. If the moderate or strong CYP3A inhibitor is discontinued, return the pexidartinib dosage (after 3 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the CYP3A inhibitor.

CYP3A Inducers: Concomitant use with moderate or strong CYP3A inducers may decrease concentrations of pexidartinib and reduce efficacy of the drug. Avoid concomitant use of pexidartinib and strong CYP3A inducers, including St. John's wort (Hypericum perforatum).

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Concomitant use of pexidartinib and substrates of CYP3A may decrease systemic exposure to the CYP3A substrate and reduce efficacy of the substrate drug. Avoid concomitant use of pexidartinib with hormonal contraceptives and other CYP3A substrates, where minimal concentration changes may lead to serious therapeutic failures. If concomitant use cannot be avoided, consult manufacturer's labeling of the CYP3A substrate drug for dosage modification recommendations.

Substrates of Other CYP Isoenzymes: Effect of pexidartinib on CYP2C8 substrates is not expected to be clinically relevant.

Drugs Affected by Uridine Diphosphate-glucuronosyltransferase

Concomitant use with uridine diphosphate-glucuronosyltransferase (UGT) inhibitors may increase concentrations of pexidartinib and increase the risk and severity of adverse reactions.

Avoid concomitant use of pexidartinib and UGT inhibitors. If concomitant use cannot be avoided, reduce the dosage of pexidartinib as described in Table 5. If the UGT inhibitor is discontinued, return the pexidartinib dosage (after 3 elimination half-lives of the UGT inhibitor) to dosage used prior to initiation of the UGT inhibitor.

Drugs Affecting Gastric Acidity

Concomitant use of pexidartinib with proton-pump inhibitors decreases pexidartinib concentrations and reduces efficacy of the drug. Effect of H₂-receptor antagonists and locally-acting antacids on pexidartinib pharmacokinetics has not been studied.

Avoid concomitant use of pexidartinib and proton-pump inhibitors. Manufacturer recommends locally-acting antacids or H₂-receptor antagonists as an alternative.

Specific Drugs

Pexidartinib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration and AUC of pexidartinib are dose proportional over a single oral dose range of 200–2400 mg.

Peak plasma concentrations attained in a median of 2.5 hours following oral administration.

Time to steady state approximately 7 days.

Food

Absorption increased by 100% when administered with high-fat meal; take on an empty stomach, either 1 hour before or 2 hours after a meal or snack.

Special Populations

Mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] with AST greater than ULN or total bilirubin >1 up to 1.5 times ULN with any AST concentration): No clinically significant effect on pharmacokinetics of pexidartinib.

Moderate hepatic impairment (total bilirubin >1.5 and up to 3 times ULN, not due to Gilbert syndrome, with any AST concentration): AUC of pexidartinib increased by 43% compared to patients with normal hepatic function.

Severe (total bilirubin greater than 3–10 times ULN and any AST concentration) hepatic impairment: Not studied.

Mild to severe renal impairment (Cl_cr 15–89 mL/minute): AUC of pexidartinib increased by approximately 30% compared to patients with normal renal function.

Distribution

Extent

Not known whether pexidartinib or its metabolites distribute into milk.

Plasma Protein Binding

Human serum albumin: 99.9%.

α-1 acid glycoprotein: 89.9%.

Elimination

Metabolism

Oxidation by CYP3A4 and glucuronidation by UGT1A4.

Elimination Route

Eliminated in feces (65% [44% unchanged drug]) and 27% in urine (≥10% as N-glucuronide).

Half-life

26.6 hours.

Stability

Storage

Oral

Capsules

20–25ºC; excursions permitted to 15–30ºC. Keep container closed and do not discard desiccant.

Actions

• Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases including colony stimulating factor 1 receptor (CSF-1R), c-Kit proto-oncogene proteins (c-Kit), and fms-like tyrosine kinase-3 (Flt-3).

• In vitro, inhibits proliferation of cell lines dependent on CSF-1R and ligand-induced autophosphorylation of CSF-1R.

• In vivo, inhibits proliferation of a CSF-1R-dependent cell line.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Instruct patients to take pexidartinib hydrochloride on an empty stomach (at least 1 hour before or 2 hours after a meal or snack). Instruct patients to swallow capsules whole (do not open, break, or chew).

• Advise patients of the risk of hepatotoxicity that could be fatal and that they will need to undergo monitoring for liver injury and to report immediately any signs or symptoms of severe liver injury to their healthcare provider.

• Pexidartinib hydrochloride is available only through a restricted program called Turalio REMS Program and patients are required to be part of the patient registry.

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

• Advise females of reproductive potential to use effective contraception during treatment with pexidartinib hydrochloride and for one month after the final dose.

• Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for one week after the final dose.

• Advise females not to breast-feed during treatment with pexidartinib hydrochloride and for one week after the final dose.

• Advise females and males of reproductive potential that pexidartinib hydrochloride may impair fertility.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

Pexidartinib hydrochloride is only available through a restricted program called Turalio REMS Program. Clinicians should consult the Turalio REMS website at [Web] or calling 833-887-2546.

Pexidartinib hydrochloride can only be obtained through a designated specialty pharmacy.

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