Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor
- PDF / 1,020,009 Bytes
- 18 Pages / 595.276 x 790.866 pts Page_size
- 89 Downloads / 173 Views
ORIGINAL RESEARCH ARTICLE
Pharmacokinetic Profile of Gilteritinib: A Novel FLT‑3 Tyrosine Kinase Inhibitor Angela Joubert James1 · Catherine C. Smith2 · Mark Litzow3 · Alexander E. Perl4 · Jessica K. Altman5 · Dale Shepard6 · Takeshi Kadokura7 · Kinya Souda7 · Melanie Patton1 · Zheng Lu1 · Chaofeng Liu1 · Selina Moy1 · Mark J. Levis8 · Erkut Bahceci1
© The Author(s) 2020
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.
1 Introduction Over 90% of leukemia cases are diagnosed in adults 20 years of age and older, among whom the most common types are chronic lymphocytic leukemia (37%) and acute myeloid leukemia (AML; 32%). [1] It was estimated that 19,520 patients
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40262-020-00888-w) contains supplementary material, which is available to authorized users. * Angela Joubert James [email protected] Extended author information available on the last page of the article
(10,380 men and 9140 women) would be diagnosed with
Data Loading...
