Pexidartinib

Uses

Pexidartinib is an antitumor agent that is used for the treatment of rare disease tenosynovial giant cell tumors (TGCT) by inhibiting colony-stimulating factor 1 and its receptor.

Pexidartinib is indicated for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

Pexidartinib is also used to associated treatment for these conditions: Symptomatic Tenosynovial Giant Cell Tumor

How Pexidartinib works

Tenosynovial giant cell tumor is a rare, non-malignant neoplasm that causes abnormal growth and damage to the synovium, bursae, or tendon sheaths. Recruitment of immune cells, specifically macrophages, is closely associated with the tumor mass formation in tenosynovial giant cell tumors. Macrophages drive tumor-promoting inflammation and play a central role in every stage of tumor progression. As the most abundant immune cells in the tumor microenvironment of solid tumors, macrophages promote processes that enhance tumor survival, such as angiogenesis, tumor cell invasion, and intravasation at the primary site. They also modulate the immune response to tumors to inhibit tumor clearance and directly engage with tumor cells to activate pro-survival signaling pathways.

The recruitment, proliferation, and irreversible differentiation of macrophages are regulated by colony-stimulating factor-1 (CSF-1), which is a cytokine that is often translocated and highly expressed in tenosynovial giant cell tumors. Elevated expression of CSF-1 and CSF-1 receptor (CSF1R) has also been implicated in various models of malignant cancers and tumors. Pexidartinib targets the CSF1/CSF1R pathway as a selective CSF1R inhibitor. It stimulates the autoinhibited state of the CSF1R by interacting with the juxtamembrane region of CSF1R, which is responsible for folding and inactivation of the kinase domain, and preventing the binding of CSF1 and ATP to the region. Without the binding of CSF1 to the receptor, CSF1R cannot undergo ligand-induced autophosphorylation. By inhibiting the CSF1R signaling pathway, pexidartinib works to inhibit tumor cell proliferation and downmodulate cells involved in the disease, such as macrophages. It was also shown to inhibit the CD117 or proto-oncogene receptor tyrosine kinase (cKIT), mutant fms-like tyrosine kinase 3 (FLT3), and platelet-derived growth factor receptor (PDGFR)-β, which are all receptor tyrosine kinases that regulate critical cellular processes such as cell proliferation and survival.

Toxicity

There is limited human data on the overdose of pexidartinib. In 4-week toxicology studies, the no-observed-adverse-effect levels (NOAELs) of pexidatrtinib were determined to be 10 mg/kg/day in rats and 6 mg/kg/day in dogs. Pexidartinib was shown to cause hepatotoxicity in clinical trials, including mixed or cholestatic hepatotoxicity, and embryo-fetal toxicity in animal studies.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of pexidartinib.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of pexidartinib and may reduce its serum concentration.
• Take on an empty stomach. Take at least 1 hour before or 2 hours after eating a meal or snack.
• Take separate from antacids. Take antacids at least 2 hours before or after pexidartinib.

[Major] ADJUST DOSING INTERVAL: The presence of food may increase the absorption and toxicity of pexidartinib.

Administration of pexidartinib with a high-fat meal increased peak plasma concentration (Cmax) and systemic exposure (AUC) by 100% and prolonged the time to reach peak plasma concentration (Tmax) by 2.5 hours.

GENERALLY AVOID: Grapefruit or grapefruit juice may increase the plasma concentration and risk of adverse effects of pexidartinib, including potentially fatal hepatotoxicity.

The mechanism is inhibition of CYP450 3A4-mediated metabolism of pexidartinib by certain compounds present in grapefruits.

Concomitant administration of itraconazole, a strong CYP450 3A4 inhibitor, increased pexidartinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 48% and 70%, respectively.

MANAGEMENT: Pexidartinib should be administered on an empty stomach, at least one hour before or two hours after a meal or snack.

Consumption of grapefruit or grapefruit juice should generally be avoided during pexidartinib therapy.

If concomitant use is unavoidable, the dose of pexidartinib should be reduced according to the manufacturer's recommendations.

If concomitant use of grapefruit or grapefruit juice is discontinued, the dose of pexidartinib may be increased (after 3 plasma half-lives of a strong CYP450 3A4 inhibitor) to the dose that was used prior to consumption of grapefruit or grapefruit juice.

Pexidartinib Alcohol interaction

[Major] GENERALLY AVOID:

Serious cases of hepatotoxicity, some fatal, have occurred in patients treated with pexidartinib.

Concomitant use of other potentially hepatotoxic agents may potentiate the risk of liver injury.

The mechanism of hepatotoxicity is unknown, its occurrence cannot be predicted, and it is unknown whether liver injury occurs in the absence of increased transaminases.

In one study, 5% of patients who received pexidartinib developed signs of serious liver injury (elevated serum transaminases greater than 3 times the upper limit of normal (ULN) and total bilirubin greater than 2 times ULN).

In these patients, peak ALT ranged from 6 to 9 times ULN, peak total bilirubin ranged from 2.5 to 15 times ULN, and ALP was greater than 2 times ULN.

Liver transaminases and total bilirubin improved to less than 2 times ULN in these patients 1 to 7 months after discontinuing pexidartinib.

The use of pexidartinib with other potentially hepatotoxic agents should be avoided.

Patients treated with pexidartinib should have liver function tests, including AST, ALT, total bilirubin, direct bilirubin, ALP, and gamma-glutamyl transferase (GGT), prior to initiation of pexidartinib, weekly for the first 8 weeks, every 2 weeks for the next month, and every 3 months thereafter.

Pexidartinib therapy may require a dosage reduction, to be withheld, or permanently discontinued based on the severity of the hepatotoxicity.

A recurrence of increased serum transaminases, bilirubin, or ALP may occur upon rechallenge with a reduced dose of pexidartinib.

Liver function tests should be performed weekly for the first month after rechallenge.

Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

Pexidartinib Disease Interaction

Major: hepatic dysfunctionModerate: renal Impairment

Volume of Distribution

The apparent volume of distribution of pexidartinib is about 187 L. In rats, pexidartinib was shown to penetrate into the central nervous system.

Elimination Route

Following administration of single doses in healthy subjects and multiple doses in patients, the mean Cmax was 8625 ng/mL and the mean AUC was 77465 ngxh/mL. The median Tmax was 2.5 hours and the time to reach the steady state was approximately 7 days. Administration of pexidartinib with a high fat meal resulted in an increased drug Cmax and AUC by 100%, with a delay in Tmax by 2.5 hours.

Half Life

The elimination half-life is about 26.6 hours.

Clearance

The apparent clearance is about 5.1 L/h.

Elimination Route

Pexidartinib is predominantly excreted via feces, where fecal excretion accounts for 65% of total pexidartinib elimination. Via this route of elimination, about 44% of the compound found in feces is recovered as unchanged parent drug. The renal elimination accounts for 27% of pexidartinib elimination, where more than 10% of the compound is found as the N-glucuronide metabolite.

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