Drug-Drug Interaction Potential of SH-1028, a Third-generation EGFR-TKI:
In Vitro and Clinical Trials
Abstract
SH-1028 is an irreversible third-generation EGFR tyrosine kinase
inhibitor (EGFR-TKI) for the treatment of locally advanced or metastatic
non-small cell lung cancer (NSCLC). Considering the possibility of
combination therapy in patients with NSCLC, we investigated the
drug-drug interaction (DDI) potential of SH-1028 both in vitro and in
clinical trials. The in vitro studies were conducted to determine the
potential of SH-1028 as a substrate, inducer, or inhibitor of cytochrome
P450 (CYP) subtypes. A phase I drug-drug interaction study in healthy
volunteers was performed to evaluate the impact of co-administering
rifampicin (a strong CYP3A4 inducer) and itraconazole (a strong CYP3A4
inhibitor) on the pharmacokinetics of SH-1028. The in vitro experiments
showed that SH-1028 was mainly metabolized by CYP3A4. The activities of
CYP1A2, 2B6, 2C19, 2D6 and 3A4 enzymes were slightly inhibited in vitro
with SH-1028. SH-1028 has no obvious induction effect on CYP1A2 and
CYP2B6 activities, but has potential induction effect on CYP3A4 mRNA
expression. However, SH-1028 may not induce or inhibit human CYPs
significantly at the clinically expected dose (200 mg). It is speculated
that itraconazole and rifampicin affect the metabolism of SH-1028. In
the clinical application of SH-1028, special attention should be paid to
the interaction between SH-1028 and drugs or foods that affect the
activity of CYP3A4.