Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor

Abstract

Background and objective: Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib.

Methods: The pharmacokinetic profile of gilteritinib was assessed from five clinical studies.

Results: Dose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20-450 mg). Median maximum concentration was reached 2-6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function.

Conclusions: Gilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment.

Clinical trial registration: NCT02014558, NCT02456883, NCT02571816.

Conflict of interest statement

Angela Joubert James, Melanie Patton, Chaofeng Liu, Selina Moy, and Erkut Bahceci are employees of Astellas Pharma, US Inc. Zheng Lu was an employee of Astellas Pharma US, Inc. during the time of the study and development of the manuscript. Takeshi Kadokura and Kinya Souda are employees of Astellas Pharma, Inc. Catherine C. Smith received research grants from Astellas Pharma US, Inc. Mark Litzow has no conflicts of interest that are directly relevant to the content of this article. Alexander E. Perl has received funding, honoraria, or travel reimbursement from Astellas, Daiichi-Sankyo, Arog, Novartis, Pfizer, Actinium Pharmaceuticals, Jazz Pharmaceuticals, Takeda, AbbVie, NewLink Genetics, Asana Biosciences, and Seattle Genetics. Jessica K. Altman has received funding, honoraria, or travel reimbursement from AbbVie, Agios, Ariad, Astellas, Bayer, BioSight, BMS, Boeringer Ingelheim, Cancer Expert Now, Celator, Celgene, Daiichi Sankyo, Epizyme, France Foundation, FujiFilm, Genentech, Glycomimetics, GSK, Incyte, Janssen Pharmaceuticals, Novartis, PeerView, Pfizer, prIME Oncology, Syros, and Theradex. Dale Shepard has received funding, honoraria, or travel reimbursement from Celgene, Sanofi, AstraZeneca, Ipsen, Amgen, Genentech, Eli Lilly, Bayer, Leap, Alkermes, Aduro, Halozyme, Ignyta, BMS, Pfizer, Kinex, and Corvus. Mark J. Levis has received funding or personal fees from Astellas, Novartis, Daiichi-Sankyo, and FujiFilm.

Figures

Fig. 1

Mean plasma gilteritinib concentrations after escalating oral doses in patients with acute myeloid leukemia (AML). Single-dose concentration–time curve (a) and multiple-dose concentration–time curve (b). Single dose (Cycle 1 Day-2), 20 mg: n = 5; 40–450 mg: n = 3. Steady state (Cycle 1 Day 15), 20 mg: n = 4; 40 mg, 80 mg, 120 mg, 300 mg: n = 3; 200 mg: n = 2; 450 mg: n = 1

Fig. 2

Median dose-normalized gilteritinib trough plasma concentration–time profiles by use of a cytochrome P450 (CYP) 3A inhibitor in patients with relapsed or refractory acute myeloid leukemia (AML)

Fig. 3

Relationship between gilteritinib trough concentration and clinical response. Numbers inside the bars represent the number (n) of patients achieving each response, while the proportion (%) of patients achieving each response is represented on the y axis. All patients who received at least one dose of the study drug for whom sufficient plasma concentration data were available to facilitate the derivation of at least one pharmacokinetic (PK) parameter, and for whom the time of dosing on the day of sampling was known, were included in the analysis. CRc composite complete response, n number of patients, NE not evaluable, NR no response, PR partial response

Fig. 4

Mean midazolam [MDZ] (a) and 1-OH midazolam (b) plasma concentration–time profiles in patients with relapsed or refractory acute myeloid leukemia (AML). Concentrations below the limit of quantification (BLQ) [lower limit of quantification (LLOQ) = 0.1 ng/mL] were set to zero. Mean was not calculated if concentration was BLQ for all subjects in a given category. Day-1, n = 15 at 24 h; Cycle 1, Day 15, n = 8 at 24 h. 1-OH 1-hydroxymidazolam

Fig. 5

Effect of gilteritinib on the pharmacokinetics of cephalexin in patients with relapsed or refractory acute myeloid leukemia (AML). Linear scale (a) and Log scale (b). Day-1, n = 20 at 24 h; Cycle 1, Day 15, n = 16 at 24 h

Fig. 6

Proposed metabolic pathway for gilteritinib

Fig. 7

Effects of strong cytochrome P450 (CYP) 3A4 inhibitors and inducers on mean gilteritinib plasma concentrations in healthy adult subjects. Concentrations below the limit of quantification (BLQ) [lower limit of quantification (LLOQ) = 0.1 ng/mL] were set to zero. Mean was not calculated if concentration was BLQ for all subjects in a given category. N = 20 for each treatment arm