The inhibitory effect of isavuconazole on almonertinib metabolism and its underlying mechanism

Abstract

As a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), almonertinib is effective for the treatment of non-small cell lung cancer (NSCLC), and there is not much interaction research on its combination with other drugs. Here, an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was validated and enabled stable and rapid determination of plasma concentrations of almonertinib and its main metabolite HAS-719. In human liver microsomes (HLMs), rat liver microsomes (RLMs) and recombinant human CYP3A4 (rCYP3A4), we found that isavuconazole as an inhibitor was able to inhibit almonertinib metabolism at medium inhibitory effect with IC₅₀ of 5.26 µM, 1.59 µM and 1.14 µM, respectively. In addition, we further investigated the mechanism of inhibition of almonertinib by isavuconazole in HLMs and RLMs in vitro as the mixed inhibitory mechanism and in rCYP3A4 with the competitive inhibition. Almonertinib's pharmacokinetic parameters, such as AUC_(0−t), CLz/F, and C_max, were significantly altered by isavuconazole in pharmacokinetic experiments in rats, but did not affect the metabolism of HAS-719. The above results showed that isavuconazole inhibited the metabolism of almonertinib in vivo and in vitro, which will alert the plasma concentration of almonertinib in clinic. Thus, the interaction between almonertinib and isavuconazole should be taken into consideration when almonertinib is used in the clinic.