Gilteritinib
Gilteritinib Uses, Dosage, Side Effects, Food Interaction and all others data.
Gilteritinib, also known as ASP2215, is a small molecule part of the FLT3 tyrosine kinase inhibitors that presented a greater selectivity and potency when compared with other agents from this group. It is a pyrazinecarboxamide derivative that showed high selectivity to FLT3 preventing the c-Kit -driven myelosuppression observed in other therapies. Gilteritinib was developed by Astellas Pharma and FDA approved on November 28, 2018. This drug was approved after being designed as an orphan drug with a fast track and priority review status.
In preclinical trials, gilteritinib demonstrate an IC50 for the wild-type receptor of 5 nM, 0.7-1.8 nM for ITD-mutated and comparable inhibition to other therapies in the TKD-mutated. As well, data showed a gilteritinib-driven inhibition of the receptor tyrosine kinase AXL which is known to modulate the activity of FLT3 in acute myeloid leukemia. Another important result in vivo was the localization in high levels in xenografted tumors which indicated high selectivity.
In phase 1/2 clinical trials, gilteritinib was shown to present a composite complete response of 41%, an overall response rate of 52%, a median duration of response of 20 weeks with a median overall survival of 31 weeks.
| Trade Name | Gilteritinib |
| Availability | Prescription only |
| Generic | Gilteritinib |
| Gilteritinib Other Names | Gilteritinib |
| Related Drugs | Xospata, Venclexta, vincristine, venetoclax, azacitidine, cytarabine, daunorubicin |
| Weight | 40mg |
| Type | Oral tablet |
| Formula | C29H44N8O3 |
| Weight | Average: 552.724 Monoisotopic: 552.353637309 |
| Protein binding | Gilteritinib is reported to be highly bound to plasma proteins, representing 94% of the dose. From this ratio, the main protein-bound is serum albumin. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Gilteritinib is an AXL receptor tyrosine kinase inhibitor used to treat relapsed or refractory acute myeloid leukemia.
Gilteritinib is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia with an FLT3 mutation detected by an FDA-approved test. This indication was expanded for a companion diagnostic to include use with gilteritinib such as the LeukoStrat CDx FLT3 Mutation Assay.
Acute myeloid leukemia is cancer that impacts the blood and bone marrow with a rapid progression. This condition produces low numbers of normal blood cells and the requirement of continuous need for transfusions.
Gilteritinib is also used to associated treatment for these conditions: Relapsed or Refractory Acute Myeloid Leukemia With FLT3 Activating Mutations
How Gilteritinib works
Gilteritinib is a potent selective inhibitor of both of the mutations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD), of the FLT3 receptor. In the same note, gilteritinib also inhibits AXL and ALK tyrosine kinases. FLT3 and AXL are molecules involved in the growth of cancer cells. The activity of gilteritinib permits an inhibition of the phosphorylation of FLT3 and its downstream targets such as STAT5, ERK and AKT.
The interest in FLT3 transmembrane tyrosine kinases was raised when studies reported that approximately 30% of the patients with acute myeloid leukemia presented a mutationally activated isoform. As well, the mutation ITD is associated with poor patient outcomes while the mutation TKD produces a resistance mechanism to FLT3 tyrosine kinase inhibitors and the AXL tyrosine kinase tends to produce a resistance mechanism to chemotherapies.
Toxicity
Gilteritinib is not reported to be mutagenic in bacterial mutagenesis assays nor clastogenic in aberration test assays in Chinese hamster lung cells. However, it resulted positive for the induction of micronuclei in mouse bone marrow and for the degeneration and necrosis of germ cells and spermatid giant cell formation in testis as well as single cell necrosis of the epididymal duct epithelia.
Food Interaction
- Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of gilteritinib.
- Avoid St. John's Wort. This herb induces CYP3A4 and p-glycoprotein, which may reduce the serum concentration of gilteritinib.
- Take at the same time every day.
- Take with or without food.
Gilteritinib Drug Interaction
Moderate: isavuconazonium, glycerin, lithiumMinor: sulfamethoxazole / trimethoprimUnknown: charcoal, ubiquinone, copper gluconate, sodium iodide, arginine, levocarnitine, cysteine, bioflavonoids, metoprolol, valproic acid, thiamine, cyanocobalamin, pyridoxine, cholecalciferol, phytonadione, menaquinone
Gilteritinib Disease Interaction
Volume of Distribution
The estimated apparent central and peripheral volume of distribution is 1092 L and 1100 L respectively. This value indicated an extensive tissue distribution.
Elimination Route
In preclinical trials, the maximal plasma concentration of gilteritinib was observed 2 hours after oral administration and followed by a maximal intratumor concentration after 4-8 hours. The maximum concentration, as well as the AUC, were modified correspondingly with the dose and were reported to be 374 ng/ml and 6943 ng.h/ml, respectively. The steady-state plasma level is reached within 15 days of dosing with an approximate 10-fold bioaccumulation.
In a fasted state in humans, the tmax is reported to be of 4-6 hours. The Cmax and AUC were decreased by 26% and 10% respectively by the co-ingestion of a high-fat meal with a tmax delay of 2 hours.
Half Life
The reported median half-life of gilteritinib was of approximate 45-159 hours.
Clearance
The estimated clearance of gilteritinib is 14.85 L/h.
Elimination Route
From the administered dose, gilteritinib is mainly excreted in feces which represents 64.5% of the administered dose while 16.4% is recovered in urine either as the unchanged drug or as its metabolites.
Innovators Monograph
You find simplified version here Gilteritinib
