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 [C]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, -demethylation, amide hydrolysis, and-demethylation. High plasma CGP52421 and CGP62221 exposures in humans, along with relatively potent cell-based IC 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%).

Simultaneous Physiologically Based Pharmacokinetic (PBPK) Modeling of Parent and Active Metabolites to Investigate Complex CYP3A4 Drug-Drug Interaction Potential: A Case Example of Midostaurin

“…First, the fraction of dose absorbed (F a ) was entered as 0.85, primarily to optimize the C max , based on the observed data from a single oral 50-mg dose of midostaurin in a prior clinical study. This F a value was consistent with the moderate to high absorption observed in preclinical species and humans (He et al, 2017). The absorption rate constant and lag time were user defined as 1.5 1/h and 0.3 hours, respectively, to optimize C max and the time at which C max is reached that were observed in several clinical trials (after a single dose).…”

“…The fractions bound to plasma for all three components were very high (.99%). For these very highly bound compounds, an equilibrium gel filtration method was used (Weiss and Gatlik, 2014;He et al, 2017). Midostaurin was mainly bound to human a1-acid glycoprotein (AGP) according to an internal study.…”

“…Furthermore, CGP52421 and CGP62221 are also metabolized mainly by CYP3A4. The human ADME study (He et al, 2017) showed that midostaurin undergoes extensive metabolism and is predominantly excreted through feces, mostly as metabolites. The fractions of CYP3A4 for the metabolism/elimination of midostaurin in human fecal excreta were estimated to be 37%, 37%, and 26% for CGP52421, CGP62221, and other minor metabolites, respectively.…”

Plasma Protein Binding of Highly Bound Drugs Determined With Equilibrium Gel Filtration of Nonradiolabeled Compounds and LC-MS/MS Detection

“…38 In addition, metabolites of PKC412 showed similar PPB phenomenon. 33 Three of the 7 compounds assayed singly were also combined into a compound pool, and the percent free for each component of the mixture was determined. The comparison summarized in Table 2 demonstrate that the results obtained with a small pool of 3 compounds and with individual assays are within the experimental uncertainties of each other and, as shown in warfarin example, maintain the same relative interspecies differences in PPB.…”

“…The proprietary compounds included nonradiolabeled versions of 3 that were previously reported NOV01, NOV04, and PKC412/Midostaurin. 24,33 The structures of PKC412 and warfarin are shown in Figure 1. The reported compounds contained 14 C, so the nonradiolabeled compounds used in this study have a 2 Da lower molecular mass.…”