INCB054828
INCB054828 Uses, Dosage, Side Effects, Food Interaction and all others data.
INCB054828 is a small molecule kinase inhibitor with antitumour activity. It works by inhibiting fibroblast growth factor receptors (FGFRs), which are receptor tyrosine kinases that activate signalling pathways in tumour cells. FGFRs gained attention as potential therapeutic targets in selected cancers, as FGFR gene alterations were observed in a wide variety of cancers including those of the urinary bladder, breast, ovary, prostate, endometrium, lung, and stomach. Deregulated FGFR signalling pathway can lead the development of oncogenes and tumour-promoting physiological processes, such as cancer cell proliferation, enhanced angiogenesis, and evasion of cell death.
In April 2020, pemigatinib was approved by the FDA for the treatment of unresectable locally advanced or metastatic cholangiocarcinoma in previously treated adult patients with a fibroblast growth factor receptor 2 (FGFR2) gene fusion or other rearrangements as detected by an FDA-approved test. Cholangiocarcinoma is the most common primary malignancy affecting the biliary tract and the second most common primary hepatic malignancy. This malignancy accounts for 15% to 20% of primary hepatobiliary malignancies, which account for 13% of overall cancer-related global mortality. With increasing research on the pathogenesis of cholangiocarcinoma and potential therapeutic targets for anticancer drug treatment, recent studies show that up to 45% of patients with intrahepatic cholangiocarcinoma exhibited gene rearrangements resulting in oncogenic fibroblast growth factor 2 (FGFR2) fusion proteins. The FDA-approved indication for pemigatinib was granted under accelerated approval based on the overall response rate and duration of response in pre-marketing clinical trials. INCB054828 is marketed under the brand name Pemazyre, and it is available as oral tablets.
INCB054828 is a small molecule kinase inhibitor that exerts anti-tumour activity through inhibition of fibroblast growth factor receptors (FGFRs). With an IC50 of less than 2 nM, pemigatinib displays potent inhibition of FGFR1, FGFR2, and FGFR3. In mouse xenograft models of human tumours with FGFR1, FGFR2, or FGFR3 alterations, pemigatinib exhibited potent anti-tumour activity by suppressing the growth of xenografted tumour models. It also showed efficacy against a patient-derived xenograft model of cholangiocarcinoma that expressed an oncogenic FGFR2 Transformer-2 beta homolog (TRA2b) fusion protein. INCB054828 also inhibited FGFR4 in vitro, however at a concentration approximately 100 times higher than those that inhibit FGFR1, 2, and 3.
| Trade Name | INCB054828 |
| Availability | Prescription only |
| Generic | Pemigatinib |
| Pemigatinib Other Names | INCB054828, Pemigatinib |
| Related Drugs | Pemazyre |
| Type | |
| Formula | C24H27F2N5O4 |
| Weight | Average: 487.508 Monoisotopic: 487.203110695 |
| Protein binding | The in vitro serum protein binding of pemigatinib was 90.6% at drug concentrations ranging from 1 to 10 µM. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
INCB054828 is a kinase inhibitor used to treat locally advanced or metastatic, unresectable cholangiocarcinoma in previously treated adult patients.
INCB054828 is indicated for the treatment of unresectable locally advanced or metastatic cholangiocarcinoma in previously-treated adult patients with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.
INCB054828 is also used to associated treatment for these conditions: Unresectable, locally advanced Cholangiocarcinomas, Unresectable, metastatic Cholangiocarcinomas
How INCB054828 works
Fibroblast growth factor receptor (FGFR) is a receptor tyrosine kinase involved in activating signalling pathways that promote cell proliferation, survival, and migration, as well as growth arrest and cellular differentiation. The initiation of the FGFR signalling pathway requires the binding of its natural ligand, fibroblast growth factor (FGF). Once FGF binds to the extracellular ligand-binding domain of the receptor, FGFRs dimerize and autophosphorylate the tyrosine residue in the intracellular tyrosine-kinase domain, leading to the activation of the tyrosine kinase. Downstream cascades involve phosphorylation of multiple intracellular signalling proteins, such as phosphatidylinositol 3 kinase (PI3K)-AKT and RAS/mitogen-activated protein kinase (MAPK), and phospholipase Cγ, which activates the protein kinase C pathway. FGFR-mediated pathway ultimately promotes cell growth, differentiation, survival, angiogenesis, and organogenesis, depending on cell type. Expressed in different isoforms in various tissues and cell lines, FGFRs are not constitutively active in normal cells. However, FGFR1, FGFR2, or FGFR3 alterations in certain tumours can lead to constitutive FGFR activation and aberrant FGFR signalling, supporting the proliferation and survival of malignant cells.
INCB054828 inhibits FGFR1, FGFR2, and FGFR3, blocking their signalling pathways and decreasing cell viability in cancer cell lines with activating FGFR amplification and fusions that resulted in constitutive activation of FGFR signalling. Genetic alterations in FGFR1, FGFR2, and FGFR3 (such as amplification, missense, or fusion mutations in the coding region) leading to constitutive activation of FGFR signalling pathways are observed in various tumours. However, alterations in FGFR genes are demonstrated in selected patients and do not always imply oncogene development. Therefore, it is imperative that fusion or rearrangement of FGFRs are demonstrated through tests prior to initiation of drug therapy.
Toxicity
There is limited information on the LD50 value and overdose profile of pemigatinib.
In animal studies, pemigatinib caused fetal harm and embryo-fetal death in pregnant rats. FDA advises nursing women to avoid breastfeeding when receiving pemigatinib. Physeal and cartilage dysplasia were present in multiple bones of rats and non-human primates with pemigatinib exposures lower than the human exposure at the clinical dose of 13.5 mg.
Food Interaction
- Avoid grapefruit products. Grapefruit may increase drug levels and adverse effects.
- Take at the same time every day.
- Take with or without food. A high-fat or high-calorie meal does not have clinically significant effects on drug concentrations.
[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of pemigatinib, which is primarily metabolized by CYP450 3A4 in vitro.
The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.
Inhibition of hepatic CYP450 3A4 may also contribute.
The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors.
When itraconazole, a potent CYP450 3A4 inhibitor, was administered following a single oral pemigatinib dose of 4.5 mg, pemigatinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 17% and 88%, respectively.
Concomitant use of moderate CYP450 3A4 inhibitors is predicted to increase pemigatinib exposure by approximately 50% to 80%.
In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.
Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.
Increased exposure to pemigatinib may increase the incidence and severity of serious adverse reactions such as hyperphosphatemia (which can cause precipitation of calcium-phosphate crystals over time that can lead to hypocalcemia, soft tissue mineralization such as cutaneous calcification and calcinosis, secondary hyperparathyroidism, anemia, muscle cramps, seizures, QT prolongation, and arrhythmias), serous retinal detachment (which may cause symptoms such as blurred vision, visual floaters, or photopsia), palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), arthralgia, stomatitis, diarrhea, nausea, vomiting, and constipation.
INCB054828 pharmacokinetics were not significantly affected by coadministration of a high-fat, high-calorie meal (approximately 1000 calories; 500 to 600 calories from fat).
MANAGEMENT: INCB054828 may be administered with or without food.
Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit extract during treatment with pemigatinib.
Volume of Distribution
The apparent volume of distribution was 235 L (60.8% CV) following a single oral dose of 13.5 mg pemigatinib.
Elimination Route
Following administration of a single oral dose of 13.5 mg pemigatinib, the median Tmax was 1.13 (0.50-6.00) hours. The steady state was reached within 4 days following repeated once daily dosing, with the median drug accumulation ratio of 1.63 (range 0.63 to 3.28). Steady-state concentration of pemigatinib increased in a dose-proportional manner over the dose range of 1 to 20 mg, which is about 0.07 to 1.5 times the recommended dose. The mean steady-state AUC and Cmax were 2620 nM x h (54% CV) and 236 nM, respectively.
Half Life
Following administration of a single oral dose of 13.5 mg pemigatinib, the geometric mean elimination half-life (t½) of pemigatinib was 15.4 (51.6% CV) hours.
Clearance
Following administration of a single oral dose of 13.5 mg pemigatinib, the geometric mean apparent clearance (CL/F) was 10.6 L/h (54% CV).
Elimination Route
Following oral administration of a single radiolabeled dose of 11 mg pemigatinib, about 82.4% of the dose was recovered in feces. Of this recovered drug, about 1.4% of the dose was unchanged parent compound. About 12.6% of the dose was recovered in urine, where 1% of the dose was unchanged.
Innovators Monograph
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