Pemigatinib is developed by Incyte Corporation, USA. In April 2020, the U.S. Food and Drug Administration (FDA) approved pemigatinib for the treatment of advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions or rearrangements.
Pemigatinib Indications
1. Treatment of previously treated adult patients with unresectable locally advanced or metastatic cholangiocarcinoma who have been confirmed by FDA-approved testing to have FGFR2 fusions or rearrangements. This indication received accelerated approval based on overall response rate and duration of response; subsequent approval is contingent on confirmatory clinical benefit validation from confirmatory trials.
2. Treatment of adult patients with relapsed or refractory FGFR1 rearranged myeloid/lymphoid neoplasms (MLNs).
Pemigatinib Dosage and Administration
1. Cholangiocarcinoma: Patients with FGFR2 gene fusions or rearrangements should undergo appropriate testing before starting medication.
The recommended dose of pemigatinib is 13.5 mg orally once daily for 14 days, followed by a 7-day break (21-day cycle), until disease progression or intolerable toxicity.
2. FGFR1 Rearranged MLNs: The recommended dose of pemigatinib is 13.5 mg orally once daily (continuously) until disease progression or intolerable toxicity.
3. Instructions for Use: Pemigatinib tablets should be swallowed whole and can be taken with food.
Depending on the severity of renal function, for patients with renal failure and an eGFR ≤ 29 mL/min, the original dose of 9 mg may be adjusted to an appropriate intermittent or continuous administration regimen.
For patients with severe hepatic impairment (especially those with a total bilirubin level more than three times the ULN), the initial dose should be reduced to 9 mg.
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Pemigatinib Dosage Forms and Strengths: Tablets in three strengths: 4.5 mg, 9 mg, and 13.5 mg.
Pemigatinib Contraindications: None.
Pemigatinib Precautions:
1. Ocular toxicity: May cause retinal pigment epithelium detachment. Optical coherence tomography (OCT) is required before administration. Follow-up examinations should be performed every 2 months for the first 6 months of treatment, and then every 3 months thereafter. Immediate examination is necessary if visual symptoms occur.
2. Hyperphosphatemia and soft tissue calcification: The dosage of the drug will be adjusted or discontinued according to the patient's serum phosphorus level to maintain a relatively stable state.
3. Embryo-fetal toxicity: There is a risk of teratogenicity; patients of childbearing age should use effective contraception.
Adverse reactions of pemigatinib:
1. Patients with cholangiocarcinoma (incidence ≥20%): Hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, taste disturbance, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, dry skin.
2. Patients with FGFR1 rearranged MLNs (incidence ≥20%): Hyperphosphatemia, nail toxicity, alopecia, stomatitis, diarrhea, dry eye, fatigue, rash, abdominal pain, anemia, constipation, dry mouth, epistaxis, serous retinal detachment, limb pain, decreased appetite, dry skin, indigestion, back pain, nausea, blurred vision, peripheral edema, dizziness.
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Pemigatinib Drug Interactions
(1) Potent/Intermediate CYP3A Inducers
Concomitant use of pemigatinib with potent or intermediate CYP3A inducers may decrease plasma concentrations of pemigatinib, potentially leading to reduced efficacy. Concomitant use of pemigatinib with potent or intermediate CYP3A inducers should be avoided.
(2) Potent/Intermediate CYP3A Inhibitors
Concomitant use of pemigatinib with potent or intermediate CYP3A inhibitors may increase plasma concentrations of pemigatinib, potentially exacerbating the incidence and severity of adverse reactions. Such concomitant use should be avoided. If unavoidable, the pemigatinib dose should be reduced.
Special Populations for Pemigatinib Use
1. Pregnancy
Based on animal studies and its mechanism of action, pemigatinib use in pregnant women may lead to fetal harm or miscarriage. There are currently no clinical data on the use of pemigatinib in pregnant women. In organogenesis, administration of pemigatinib to pregnant rats (with plasma exposure lower than the human exposure of 13.5 mg clinical dose) still resulted in fetal malformations, growth retardation, and embryonic death. Pregnant women should be informed of the potential risks to the fetus.
In the general U.S. population, the background risk of major birth defects in clinically confirmed pregnancies is 2%–4%, and the risk of spontaneous abortion is 15%–20%.
2. Lactation
There are no data on the levels of pemigatinib and its metabolites in breast milk or their effects on infants. Given the potential for serious adverse reactions to breastfed infants from pemigatinib, it is recommended to discontinue breastfeeding during treatment and for one week after the last dose.
3. Women/Men of Fertility Potential: Pemigatinib use in pregnant women may cause fetal harm.
Women should use effective contraception during treatment and for one week after the last dose.
Men with female partners of fertility potential should use effective contraception during treatment and for one week after the last dose.
4. Pediatric Use: The safety and efficacy of pemigatinib in pediatric patients have not been established.
5. Elderly Use: There is no overall difference in safety and efficacy between elderly and younger patients.
6. Renal Impairment: Patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m², estimated according to the MDRD equation) require dose reduction.
Mild to moderate renal impairment (eGFR 30-89 mL/min/1.73 m²): No dose adjustment is required.
End-stage renal disease (eGFR < 15 mL/min/1.73 m²) patients undergoing intermittent hemodialysis: No dose adjustment required.
7. Hepatic Impairment
Severe hepatic impairment (total bilirubin > 3 × ULN with any elevated AST): Dose reduction required.
Mild to moderate hepatic impairment:
Mild (total bilirubin > ULN to 1.5 × ULN or AST > ULN) and moderate (total bilirubin > 1.5-3 × ULN with any elevated AST) patients do not require dose adjustment.
Storage of Pemigatinib: Store pemigatinib tablets at room temperature (20°C to 25°C); allow for temperature fluctuations of 15°C to 30°C.
Pharmacokinetics of Pemigatinib: After a once-daily oral administration of 13.5 mg, the steady-state AUC0-24h geometric mean (CV%) of pemigatinib is 2620 nM·h (54%), and the Cmax is 236 nM (56%). Steady-state concentrations of pemigatinib increase proportionally within a dose range of 1 to 20 mg (0.07 to 1.5 times the recommended dose). Steady-state concentrations of pemigatinib are reached within 4 days, and the median accumulation ratio after repeated once-daily dosing is 1.63 (range 0.63 to 3.28).
(1) Absorption: The median time to reach peak plasma concentration (Tmax) of pemigatinib was 1.13 (0.50–6.00) hours.
Effect of Food:
Co-administration of pemigatinib with a high-fat, high-calorie diet (approximately 1000 calories, of which 150 calories are from protein, 250 calories from carbohydrates, and 500–600 calories from fat) had no clinically significant effect on the pharmacokinetics of pemigatinib.
(2) Distribution: Following an oral dose of 13.5 mg, the estimated apparent volume of distribution was 235 L (60.8%). Protein binding of pemigatinib was 90.6%, independent of in vitro concentrations.
(3) Elimination: The geometrically mean (%CV) elimination half-life (t½) of pemigatinib was 15.4 (51.6%) hours, and the geometrically mean apparent clearance (CL/F) was 10.6 L/h (54%).
(4) Metabolism: Pemigatinib is primarily metabolized via CYP3A4 in vitro. The main drug-related component in plasma is unmodified pemigatinib.
(5) Excretion: Following a single oral dose of 11 mg of radiolabeled pemigatinib, 82.4% of the dose was recovered in feces (1.4% unmodified) and 12.6% of the dose was recovered in urine (1% unmodified).
