Table 3.

Midostaurin’s major pharmacokinetic and pharmacodynamic properties

Names	N-benzoyl-staurosporine CGP 41251 PKC412 Midostaurin
In vitro properties	Inhibits PDGFR, cdk1, src, fgr, syk, c-kit, VEGFR, and LT3 Induces cell cycle arrest and inhibits proliferation Radiosensitizes cell lines with p53 mutations Reverses MDR phenotype
FLT3-specific activities	Inhibits autophosphorylation of FLT3’s cytoplasmic tail Inhibits ligand-induced FLT3 phosphorylation (WT) Inhibits ligand-independent FLT3 phosphorylation (FLT3 mutants)
Clinical trial correlatives	ERK phosphorylation (downstream of PKC) FLT3 phosphorylation
Plasma protein binding	α1-Acidic glycoprotein (95%–98%)
Major metabolites	CGP 52421 (epimers e1, e2) – 7-hydroxyl products, longer t1/2 CGP 62221 – O-demethylation product, similar t1/2
Resistance mechanisms	FLT3-ITD overexpression 13q alterations Global upregulation of antiapoptotic genes Global downregulation of proapoptotic genes N676K mutation

Notes: Data from these studies.³,¹⁰,¹¹,²¹,²⁸,²⁹

Abbreviations: PKC, protein kinase C; FLT3, fms-like tyrosine kinase; ITD, internal tandem duplication; WT, wild type; MDR, multidrug resistant.