title: Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug.
abstract: The absorption, metabolism, and excretion of midostaurin, a potent class III tyrosine protein kinase inhibitor for acute myelogenous leukemia, were evaluated in healthy subjects. A microemulsion formulation was chosen to optimize absorption. After a 50-mg [14C]midostaurin dose, oral absorption was high (>90%) and relatively rapid. In plasma, the major circulating components were midostaurin (22%), CGP52421 (32.7%), and CGP62221 (27.7%). Long plasma half-lives were observed for midostaurin (20.3 hours), CGP52421 (495 hours), and CGP62221 (33.4 hours). Through careful mass-balance study design, the recovery achieved was good (81.6%), despite the long radioactivity half-lives. Most of the radioactive dose was recovered in feces (77.6%) mainly as metabolites, because only 3.43% was unchanged, suggesting mainly hepatic metabolism. Renal elimination was minor (4%). Midostaurin metabolism pathways involved hydroxylation,O-demethylation, amide hydrolysis, andN-demethylation. High plasma CGP52421 and CGP62221 exposures in humans, along with relatively potent cell-based IC50for FMS-like tyrosine kinase 3-internal tandem duplications inhibition, suggested that the antileukemic activity in AML patients may also be maintained by the metabolites. Very high plasma protein binding (>99%) required equilibrium gel filtration to identify differences between humans and animals. Because midostaurin, CGP52421, and CGP62221 are metabolized mainly by CYP3A4 and are inhibitors/inducers for CYP3A, potential drug-drug interactions with mainly CYP3A4 modulators/CYP3A substrates could be expected. Given its low aqueous solubility, high oral absorption and extensive metabolism (>90%), midostaurin is a Biopharmaceutics Classification System/Biopharmaceutics Drug Disposition Classification System (BDDCS) class II drug in human, consistent with rat BDDCS in vivo data showing high absorption (>90%) and extensive metabolism (>90%).
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey handan.he@novartis.com.
authors.forename: Handan
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey.
authors.forename: Phi
authors.initials: P
authors.lastname: Tran
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey.
authors.forename: Helen
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey.
authors.forename: Vivienne
authors.initials: V
authors.lastname: Tedesco
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey.
authors.forename: Wen
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey.
authors.forename: Ewa
authors.initials: E
authors.lastname: Gatlik
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey.
authors.forename: Kai
authors.initials: K
authors.lastname: Klein
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey.
authors.forename: Tycho
authors.initials: T
authors.lastname: Heimbach
mesh_terms: D000328:Adult; D000818:Animals; D004285:Dogs; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D055815:Young Adult
chemical_list: C586021:CGP 52421; C586020:CGP 62221; D047428:Protein Kinase Inhibitors; D019311:Staurosporine; C059539:midostaurin