Effects of dacomitinib on the pharmacokinetics of poziotinib in vivo and in vitro

Abstract

Context: Dacomitinib and poziotinib, irreversible ErbB family blockers, are often used for treatment of non-small cell lung cancer (NSCLC) in the clinic. Objective: This study investigates the effect of dacomitinib on the pharmacokinetics of poziotinib in rats. Materials and methods: Twelve Sprague-Dawley rats were randomly divided into two groups: the test group (20 mg/kg dacomitinib for 14 consecutive days) and the control group (equal amounts of vehicle). Each group was given an oral dose of 10 mg/kg poziotinib 30 min after administration of dacomitinib or vehicle at the end of the 14 day administration. The concentration of poziotinib in plasma was quantified by UPLC-MS/MS. Both in vitro effects of dacomitinib on poziotinib and the mechanism of the observed inhibition were studied in rat liver microsomes and human liver microsomes. Results: When orally administered, dacomitinib increased the AUC, T max and decreased CL of poziotinib (p < 0.05). The IC 50 values of M1 in RLM, HLM and CYP3A4 were 11.36, 30.49 and 19.57 mM, respectively. The IC 50 values of M2 in RLM, HLM and CYP2D6 were 43.69, 0.34 and 0.11 mM, respectively, and dacomitinib inhibited poziotinib by a mixed way in CYP3A4 and CYP2D6. The results of the in vivo experiments were consistent with those of the in vitro experiments. Conclusions: This research demonstrates that a drug-drug interaction between poziotinib and dacomitinib possibly exists when readministered with poziotinib; thus, clinicians should pay attention to the resulting changes in pharmacokinetic parameters and accordingly, adjust the dose of poziotinib in clinical settings.

Inhibitory effect of Schisandrin on the pharmacokinetics of poziotinib in vivo and in vitro by UPLC‐MS/MS

“…The precision, accuracy and recovery of poziotinib in samples have been tested and verified in our previous study 9 A representative chromatogram of plasma sample at 1 h after oral administration of poziotinib in rats is shown in Figure 1 . Figure 2 shows the mean plasma concentration‐time curves of poziotinib in rats after single oral administration of 2 mg/kg poziotinib or pretreatment with Schisandrins.…”

“…In liver microsomes incubation system, 10 poziotinib metabolites (M1‐M10) were measured, and dihydroxylation (M1) and demethylation (M2) were mainly metabolized by CYP3A4 and 2D6, respectively 7 . The chemical structures of poziotinib, M1 and M2 have been presented in a previous report 9 . Wang et al observed that poziotinib inhibited the enzymatic activity of CYP2B1 and 2C11 to varying levels without concentration‐dependence or time‐dependence via in vitro and in vivo experiments 8 .…”

“… 7 The chemical structures of poziotinib, M1 and M2 have been presented in a previous report. 9 Wang et al observed that poziotinib inhibited the enzymatic activity of CYP2B1 and 2C11 to varying levels without concentration‐dependence or time‐dependence via in vitro and in vivo experiments. 8 In addition, our previous study showed that the AUC (0–t) value of poziotinib was dramatically increased ( p < 0.01), while CL value of poziotinib was decreased ( p < 0.01) in rats, compared with the control group when 20 mg/kg dacomitinib (a CYP2D6 inhibitor) were long preadministered.…”

“… 8 In addition, our previous study showed that the AUC (0–t) value of poziotinib was dramatically increased ( p < 0.01), while CL value of poziotinib was decreased ( p < 0.01) in rats, compared with the control group when 20 mg/kg dacomitinib (a CYP2D6 inhibitor) were long preadministered. 9 Therefore, taken together with CYP450 enzyme inducers or inhibitors may cause pharmacokinetic changes of poziotinib and may increase the risk of adverse reactions in vivo.…”

Comprehensive analysis of m5C-Related lncRNAs in the prognosis and immune landscape of hepatocellular carcinoma

“…Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is used to treat some types of non-small cell lung cancer and advanced pancreatic cancer ( Carter et al, 2022 ). Vorinostat ( Lin et al, 2021 ), dacomitinib ( Ji et al, 2021 ), vandetanib ( Carvalho et al, 2022 ), afatinib ( Wu et al, 2021 ), and vismodegib ( Duplaine et al, 2021 ) also have anticancer effects in malignancies. In the future, further experiments are required to confirm their therapeutic potential for the targeted therapy of HCC.…”