Alflutinib (AST2818), primarily metabolized by CYP3A4, is a potent CYP3A4 inducer

Abstract

Alflutinib (AST2818) is a third-generation epidermal growth factor receptor (EGFR) inhibitor that inhibits both EGFR-sensitive mutations and T790M mutations. Previous study has shown that after multiple dosages, alflutinib exhibits nonlinear pharmacokinetics and displays a time- and dose-dependent increase in the apparent clearance, probably due to its self-induction of cytochrome P450 (CYP) enzyme. In this study, we investigated the CYP isozymes involved in the metabolism of alflutinib and evaluated the enzyme inhibition and induction potential of alflutinib and its metabolites. The data showed that alflutinib in human liver microsomes (HLMs) was metabolized mainly by CYP3A4, which could catalyze the formation of AST5902. Alflutinib did not inhibit CYP isozymes in HLMs but could induce CYP3A4 in human hepatocytes. Rifampin is a known strong CYP3A4 inducer and is recommended by the FDA as a positive control in the CYP3A4 induction assay. We found that the induction potential of alflutinib was comparable to that of rifampin. The E max of CYP3A4 induction by alflutinib in three lots of human hepatocytes were 9.24-, 11.2-, and 10.4-fold, while the fold-induction of rifampin (10 μM) were 7.22-, 19.4- and 9.46-fold, respectively. The EC 50 of alflutinib-induced CYP3A4 mRNA expression was 0.25 μM, which was similar to that of rifampin. In addition, AST5902 exhibited much weak CYP3A4 induction potential compared to alflutinib. Given the plasma exposure of alflutinib and AST5902, both are likely to affect the pharmacokinetics of CYP3A4 substrates. Considering that alflutinib is a CYP3A4 substrate and a potent CYP3A4 inducer, drug–drug interactions are expected during alflutinib treatment.

Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

“…AST5902 is the major metabolite of alflutinib (52%) and can also be induced by CYP3A4. 27 A phase 2 trial of alflutinib (ALSC003) enrolled a total of 220 centrally confirmed Chinese patients with EGFR T790Mþ NSCLC, among whom 39.5% had brain metastasis by IRC. At the time of the data cutoff (January 2020), the IRC-ORR was 74.1% (95% CI: 67.8-79.7) (163 of 220) (Fig.…”

Determination of Osimertinib, Aumolertinib, and Furmonertinib in Human Plasma for Therapeutic Drug Monitoring by UPLC-MS/MS

“…A correlation between the plasma concentration of some TKIs and the occurrence of drug-related AEs and resistance to therapy was described by Yu et al [ 16 ]. Plasma concentrations of osimertinib, aumolertinib, and furmonertinib can be affected by various factors such as pathophysiology, genetic polymorphisms, patient adherence to therapy, and interacting medications [ 17 , 18 , 19 , 20 ], leading to large inter-patient variability in efficacy and AEs. Therefore, it is necessary to monitor disease response and plasma drug concentrations to improve patient outcomes [ 21 ].…”

Genetic landscape of 125 pharmacogenes in Chinese from the Chinese Millionome Database

“…Genetic variability of the well-known pharmacogenes alleles could explain only part of the inter-individual differences in drug responses, and rare genetic variants in pharmacogenes such as SLC30A8 could modulate antidepressant (desipramine or fluoxetine) treatment 17 . The potential role on the disease development and drug efficacy of the rare variants in these genetically polymorphic pharmacogenes would be interesting and needed to be studied further 18 , 19 . The present study demonstrated that 91.1% of the 617 deleterious missense variants in the 125 pharmacogenes were rare (Fig.…”