Class:
- Oral CSF1R (colony-stimulating factor 1 receptor) inhibitor
- Also inhibits KIT and FLT3
Mechanism of Action:
- Blocks CSF1R signaling → reduces macrophage recruitment and proliferation in the synovium.
- Directly targets the CSF1 overexpression driver in TGCT.
Indication:
- FDA approved (2019) for symptomatic tenosynovial giant cell tumor (TGCT) in adults that is not amenable to surgery.
- Only systemic drug approved for TGCT.
Dose & Administration:
- 400 mg orally twice daily with a low-fat meal (≤30% fat, ~11–14 g).
- Dose adjustments required for hepatotoxicity or drug interactions.
- Metabolism: mainly CYP3A4, UGT1A4.
- Half-life: ~26 hours.
- Elimination: feces (~65%), urine (~27%).
Adverse Effects (common):
- Hair color changes (depigmentation), fatigue, nausea, vomiting, constipation, ↑cholesterol, edema.
- Hepatotoxicity (boxed warning): elevated AST/ALT, ALP, bilirubin → risk of serious, potentially fatal liver injury.
Monitoring:
- Baseline, weekly x 8 weeks, q2 weeks x 1 month, then monthly LFTs.
- Monitor for symptoms of liver dysfunction (jaundice, dark urine, right upper quadrant pain).
- CBC and renal function periodically.
Drug Interactions:
- CYP3A4 substrate → avoid strong CYP3A4 inhibitors/inducers.
- UGT inhibitors can ↑ exposure.
- Acid-reducing agents (PPIs, H2 blockers, antacids) can ↓ absorption.
- Take with low-fat meal (high-fat meals ↑ exposure 100%).
Special Considerations:
- REMS program required due to hepatotoxicity risk.
- Embryo-fetal toxicity → contraception needed during and after therapy (females: 1 month; males: 1 week).
Clinical Trial (ENLIVEN):
- Phase III trial → Pexidartinib showed significant improvement in overall response rate (39% vs 0% with placebo at 25 weeks) and functional outcomes in TGCT patients.
High-yield pharmacist points: