of gilteritinib activeingredient as free base (corresponding to 44.2 mg gilteritinib fumarate). The inactive ingredients are mannitol,hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, hypromellose, talc, polyethyleneglycol, titanium dioxide and ferric oxide.
12 CLINICAL PHARMACOLOGY
12.1 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 exogenouslyexpressing 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.
12.2 Pharmacodynamics
In patients with relapsed or refractory AML administered gilteritinib 120 mg, substantial (>90%) inhibition of FLT3phosphorylation was rapid (within 24 hours after first dose) and sustained, as characterized by an ex vivo plasmainhibitory activity (PIA) assay.
Cardiac Electrophysiology
The effect of XOSPATA 120 mg once a day on the QTc interval has been eva luated in patients, which showed an absenceof large mean increases (i.e., 20 msec) in the QTc interval.
Of 292 patients treated with gilteritinib at 120 mg tested in clinical trials, 4 patients (1.4%) experienced a QTcF >500msec. Additionally, across all doses, 2.4% of relapse/refractory subjects had a maximum post baseline QTcF interval>500 msec [see Warnings and Precautions (5.2)].
12.3 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 reachedwithin 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 post dose in thefasted state.
Effect of Food
In healthy adults administered a single gilteritinib 40 mg dose (0.3 times the recommended dosage), gilteritinib Cmaxdecreased by 26% and AUC decreased by less than 10% when co-administered with a high-fat meal (approximately 800to 1,000 total calories with 500 to 600 fat calories, 250 carbohydrate calories, 150 protein calories) compared to a fastedstate. 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%) and1100 L (4.99%), respectively, which may indicate extensive tissue distribution. In vivo, gilteritinib is approximately 94%bound to human plasma proteins. In vitro, gilteritinib is primarily bound to human serum albumin.
Elimination
The estimated half-life of gilteritinib is 113 hours, and the estimated apparent clearance is 14.85 L/h.
Metabolism
Gilteritinib is primarily metabolized via CYP3A4 in vitro. At steady state, the primary metabolites in humans includeM17 (formed via N-dealkylation and oxidation), M16 and M10 (both formed v |
