Pexidartinib

Class:

Mechanism of Action:

  • Blocks CSF1R signaling → reduces macrophage recruitment and proliferation in the synovium.
  • Directly targets the CSF1 overexpression driver in TGCT.

Indication:

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.

Pharmacokinetics:

  • 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:

  • Only systemic FDA-approved option for TGCT.
  • Boxed warning: hepatotoxicity → strict LFT monitoring and REMS.
  • Must be taken with a low-fat meal to balance absorption and safety.
  • Watch for drug interactions (CYP3A4, UGT, acid suppressants).
Links