Itraconazole and rifampicin, as CYP3A modulators but not P-gp modulators, affect the pharmacokinetics of almonertinib and active metabolite HAS-719 in healthy volunteers.
Acta Pharmacol Sin
; 43(4): 1082-1090, 2022 Apr.
Article
em En
| MEDLINE
| ID: mdl-34267345
ABSTRACT
Almonertinib is a novel third-generation EGFR tyrosine kinase inhibitor. It is mainly metabolized by CYP3A in vitro, and N-desmethylated almonertinib (HAS-719) is the major active metabolite in human plasma. In this study, we investigated the effects of CYP3A inhibitor itraconazole and CYP3A inducer rifampicin on the pharmacokinetics of almonertinib and HAS-719 in 64 healthy volunteers. We found that when co-administered with itraconazole, the maximal plasma concentration (Cmax) and the plasma exposure (AUC0-t) of almonertinib were increased by 56.3% and 2.38-fold, respectively, whereas the Cmax and AUC0-t of HAS-719 were reduced by 86.8% and 71.8%, respectively. Co-administration with rifampicin reduced the Cmax and AUC0-t of almonertinib by 79.3% and 92.6%, but the AUC0-t of HAS-719 was unexpectedly decreased by 72.5%. In vitro assays showed that both almonertinib and HAS-719 were substrates of CYP3A and P-gp. Co-administration of rifampicin in Beagle dogs reduced the fecal recovery of almonertinib and HAS-719, and markedly increased the levels of metabolites derived from further metabolism of HAS-719, which was consistent with human plasma data, suggesting that although rifampicin was also a potent inducer of P-gp, the pharmacokinetic alternation of HAS-719 was mainly due to its further metabolism but not excretion changes. Moreover, we revealed that almonertinib was a moderately sensitive substrate of CYP3A in vivo. Special attention should be paid to the interaction between almonertinib and drugs or food affecting CYP3A activity in the clinical application of almonertinib.
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MEDLINE
Assunto principal:
Rifampina
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Itraconazol
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Animals
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Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article