Studies on the inhibitory effect of isavuconazole on flumatinib metabolism in vitro and in vivo

Abstract

As the validated agent for the treatment of chronic myelogenous leukemia (CML), flumatinib is a novel oral tyrosine kinase inhibitor (TKI) with higher potency and selectivity for BCR-ABL1 kinase compared to imatinib. Many patients experience aspergillosis infection and they may start using isavuconazole, which is an inhibitor of CYP3A4. However, there is no study on their interaction in vitro and in vivo. In the present study, the concentrations of flumatinib and its major metabolite M1 were rapidly determined using an stable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The half-maximal inhibitory concentration (IC50) was 6.66 μM in human liver microsomes (HLM), while 0.62 μM in rat liver microsomes (RLM) and 2.90 μM in recombinant human CYP3A4 (rCYP3A4). Furthermore, the mechanisms of inhibition of flumatinib in human liver microsomes, rat liver microsomes and rCYP3A4 by isavuconazole were mixed. Moreover, ketoconazole, posaconazole, and isavuconazole showed more potent inhibitory effects than itraconazole, fluconazole, and voriconazole on HLM-mediated flumatinib metabolism. In pharmacokinetic experiments of rats, it was observed that isavuconazole could greatly change the pharmacokinetic parameters of flumatinib, including AUC(0−t), AUC(0−∞), Cmax and CLz/F, but had no effect on the metabolism of M1. According to the results of in vitro and in vivo studies, the metabolism of flumatinib was inhibited by isavuconazole, suggesting that isavuconazole may raise the plasma concentration of flumatinib. Thus, it is important to take special care of the interactions between flumatinib and isavuconazole in clinical applications.

Evaluation of the inhibitory effect of azoles on pharmacokinetics of lenvatinib in rats both in vivo and in vitro by UPLC‐MS/MS

“…When coadministered with posaconazole, the AUC (0− t ) , AUC (0−∞) , C max , and Tmax of posaconazole were significantly increased, and plasma clearance was decreased 33 . Liu et al evaluated the drug interaction between isavuconazole and flumatinib by three sets of hepatic microsomal models, HLMs, RLMs and recombinant human CYP3A4, respectively 34 . It has been shown that both ketoconazole and itraconazole inhibit the in vivo metabolism of alpelisib 35 .…”

“…33 Liu et al evaluated the drug interaction between isavuconazole and flumatinib by three sets of hepatic microsomal models, HLMs, RLMs and recombinant human CYP3A4, respectively. 34 It has been shown that both ketoconazole and itraconazole inhibit the in vivo metabolism of alpelisib. 35 Posazonazole differs from other triazole antifungals in that it is barely metabolized by the CYP450 pathway and 17% is glucuronidated by UGT1A4.…”

Ultra‐high‐performance liquid chromatography–quadrupole time of flight tandem mass spectrometry based in vitro metabolite profiling of DK‐GV‐04P, a novel anticancer molecule under drug discovery

“…Moreover, the importance of carrying out early metabolism studies has been felt in recent times owing to the rising concern about metabolite‐induced toxicity (Park et al, 2005, Rachmale, Rajput, Jadav, Sahu, Sharma, & Sengupta, 2022, Rachmale, Rajput, Jadav, Sahu, Tekade, & Sengupta, 2022). Generally, estimation of metabolites during the early drug discovery stage is carried out employing in vitro systems like rat liver microsomes/human liver microsomes (HLM), hepatocytes, liver slices or human S9 fractions (HS9) (Li et al, 2020, Liu et al, 2023, Panday et al, 2021, Wang et al, 2020). Such studies provide an advantage in reducing the attrition rate of drug molecules at the later phase of development.…”