ia N-dealkylation). None of these 3metabolites exceeded 10% of overall parent exposure.
Excretion
After a single radiolabeled dose, gilteritinib is excreted in feces with 64.5% of the total administered dose recovered in
feces. Of the total radiolabeled dose of gilteritinib, 16.4% was recovered in urine as unchanged drug and metabolites.
Specific Populations
Age (20-87 years), sex, race, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment and mild
(creatinine clearance (CLCr) 50-80 mL/min) or moderate (CLCr 30-50 mL/min) renal impairment do not have clinically
meaningful effects on the pharmacokinetics of gilteritinib.
The effect of severe hepatic (Child-Pugh Class C) or severe renal impairment (CLCr ≤ 29 mL/min) on gilteritinib
pharmacokinetics is unknown.
Drug Interaction Studies
Clinical Studies
Combined P-gp and Strong CYP3A Inducers:
Gilteritinib Cmax decreased approximately 30% and AUC decreased approximately 70% when co-administered withrifampin (a combined P-gp and strong CYP3A inducer).
Strong CYP3A Inhibitors:
Gilteritinib Cmax increased approximately 20% and AUC increased approximately 120% when co-administered withitraconazole (a strong CYP3A inhibitor).
Moderate CYP3A Inhibitors:
Gilteritinib Cmax increased approximately 16% and AUC increased approximately 40% when co-administered withfluconazole (a moderate CYP3A inhibitor).
CYP3A Substrates:
Midazolam (a CYP3A substrate) Cmax and AUC increased approximately 10% when co-administered with gilteritinib.
MATE1 Substrates:
Cephalexin (a MATE1 substrate) Cmax and AUC decreased by less than 10% when co-administered with gilteritinib.
In Vitro Studies
Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs that
target these receptors such as escitalopram, fluoxetine, sertraline.
Gilteritinib is a substrate of P-gp transporter and has the potential to inhibit breast cancer resistance protein (BCRP) andorganic cation transporter 1 (OCT1) transporters.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity studies have not been performed with gilteritinib.
Gilteritinib was not mutagenic in a bacterial mutagenesis (Ames) assay and was not clastogenic in a chromosomeaberration test assay in Chinese hamster lung cells. Gilteritinib was positive for the induction of micronuclei in mouse
bone marrow cells from 65 mg/kg (195 mg/m2
) the mid dose tested (approximately 2.6 times the recommended human
dose of 120 mg).
The effect of XOSPATA on human fertility is unknown. Administration of 10 mg/kg/day gilteritinib in the 4-week study
in dogs (12 days of dosing) resulted in degeneration and necrosis of germ cells and spermatid giant cell formation in the
testis as well as single cell necrosis of the epididymal duct epithelia of the epididymal head.
13.2 Animal Toxicology and/or Pharmacology
In the 13-week oral repeated dose toxicity studies in rats and dogs, target organs of toxicity included the eye and kidney.
14 CLINICAL STUDIES
14.1 Relapsed or Refractory Acute Myeloid Leukemia
The efficacy of XOSPATA was assessed in the ADMIRAL trial (NCT02421939), which included 138 adult patients withrelapsed or refractory AML having a FLT3 ITD, D835, or I836 mutation by the LeukoStrat CDx FLT3 Mutation Assay.
The cli
