Description
COMPOSITION
Gilternib tablet: Each film coated tablet contains Gilteritinib
Fumarate INN equivalent to Gilteritinib 40 mg.
PHARMACOLOGY
Mechanism of Action
Gilteritinib is a small molecule that inhibits multiple receptor tyrosine
kinases, including FMS-like tyrosine kinase 3 (FLT3). Gilteritinib
demonstrated the ability to inhibit FLT3 receptor signaling and
proliferation in cells exogenously expressing FLT3 including
FLT3-ITD, tyrosine kinase domain mutations (TKD) FLT3-D835Y and
FLT3-ITD-D835Y, and it induced apoptosis in leukemic cells
expressing FLT3-ITD.
Pharmacodynamics In patients with relapsed or refractory AML
administered Gilteritinib 120 mg, substantial (>90%) inhibition of
FLT3 phosphorylation was rapid (within 24 hours after first dose) and
sustained, as characterized by an ex vivo plasma inhibitory activity
(PIA) assay.
Cardiac Electrophysiology
The effect of GILTERITINIB 120 mg once a day on the QTc interval
has been evaluated in patients, which showed an absence of large
mean increases (i.e., 20 msec) in the QTc interval. Of 317 patients
with a post-baseline QTc measurement on treatment with Gilteritinib
at 120 mg in clinical trials, 4 patients (1.3%) experienced a QTcF
>500 msec. Additionally, across all doses 2.3% of patients with
relapse/refractory AML had a maximum post-baseline QTcF interval
>500 msec.
Pharmacokinetics
The following pharmacokinetic parameters were observed following
administration of Gilteritinib 120 mg once daily, unless otherwise
specified. Gilteritinib exposure (Cmax and AUC24) increases
proportionally with once daily doses ranging from 20 mg to 450 mg
(0.17 to 3.75 times the recommended dosage) in patients with
relapsed or refractory AML. Gilteritinib mean (±SD) steady-state
Cmax is 374 ng/mL (±190) and AUC24 is 6943 ng.hr/mL (±3221).
Steady-state plasma levels are reached within 15 days of dosing with
an approximate 10-fold accumulation.
Absorption
The time to maximum Gilteritinib concentration (tmax) observed is
approximately between 4 and 6 hours postdose in the fasted state.
Effect of Food
In healthy adults administered a single Gilteritinib 40 mg dose (0.3
times the recommended dosage), Gilteritinib Cmax decreased by
26% and AUC decreased by less than 10% when co-administered
with a high-fat meal (approximately 800 to 1,000 total calories with
500 to 600 fat calories, 250 carbohydrate calories, 150 protein
calories) compared to a fasted state. Median tmax was delayed 2
hours when Gilteritinib was administered with a high-fat meal.
Distribution
The population mean (%CV) estimates of apparent central and
peripheral volume of distribution were 1092 L (9.22%) and 1100 L
(4.99%), respectively, which may indicate extensive tissue distribu-
tion. In vivo, Gilteritinib is approximately 94% bound to human plasma
proteins. In vitro, Gilteritinib is primarily bound to human serum
albumin.
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