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.
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He H, Tran P, Gu H, Tedesco V, Zhang J, Lin W, Gatlik E, Klein K, Heimbach T
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.
Drug Metab Dispos. 2017 May;45(5):540-555. doi: 10.1124/dmd.116.072744. Epub 2017 Mar 7.
- PubMed ID
- 28270565 [ View in PubMed]
- 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, and N-demethylation. High plasma CGP52421 and CGP62221 exposures in humans, along with relatively potent cell-based IC50 for 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%).
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Midostaurin Cytochrome P450 1A2 Protein Humans UnknownInhibitorInducerDetails Midostaurin Cytochrome P450 2B6 Protein Humans UnknownInducerDetails Midostaurin Cytochrome P450 2C19 Protein Humans UnknownInhibitorInducerDetails Midostaurin Cytochrome P450 2C8 Protein Humans UnknownInhibitorInducerDetails Midostaurin Cytochrome P450 2C9 Protein Humans UnknownInhibitorInducerDetails Midostaurin Cytochrome P450 2D6 Protein Humans UnknownInhibitorDetails Midostaurin Cytochrome P450 2E1 Protein Humans UnknownInhibitorDetails Midostaurin Cytochrome P450 3A Subfamily (Protein Group) Protein group Humans UnknownSubstrateInhibitorInducerDetails Midostaurin Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorInducerDetails