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Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by alveolar epithelial cell injury and lung fibroblast overactivation. At present, only two drugs are approved by the FDA for the treatment of IPF, including the synthetic pyridinone drug, pirfenidone, and the tyrosine kinase inhibitor, nintedanib. Avitinib (AVB) is a novel oral and potent third-generation tyrosine kinase inhibitor for treating non-small cell lung cancer (NSCLC). However, the role of avitinib in pulmonary fibrosis has not yet been established. In the present study, we used in vivo and in vitro models to evaluate the role of avitinib in pulmonary fibrosis. In vivo experiments first verified that avitinib significantly alleviated bleomycin-induced pulmonary fibrosis in mice. Further in vitro molecular studies indicated that avitinib inhibited myofibroblast activation, migration and extracellular matrix (ECM) production in NIH-3T3 cells, mainly by inhibiting the TGF-β1/Smad3 signalling pathways. The cellular experiments also indicated that avitinib improved alveolar epithelial cell injury in A549 cells. In conclusion, the present findings demonstrated that avitinib attenuates bleomycin-induced pulmonary fibrosis in mice by inhibiting alveolar epithelial cell injury and myofibroblast activation.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by alveolar epithelial cell injury and lung fibroblast overactivation. At present, only two drugs are approved by the FDA for the treatment of IPF, including the synthetic pyridinone drug, pirfenidone, and the tyrosine kinase inhibitor, nintedanib. Avitinib (AVB) is a novel oral and potent third-generation tyrosine kinase inhibitor for treating non-small cell lung cancer (NSCLC). However, the role of avitinib in pulmonary fibrosis has not yet been established. In the present study, we used in vivo and in vitro models to evaluate the role of avitinib in pulmonary fibrosis. In vivo experiments first verified that avitinib significantly alleviated bleomycin-induced pulmonary fibrosis in mice. Further in vitro molecular studies indicated that avitinib inhibited myofibroblast activation, migration and extracellular matrix (ECM) production in NIH-3T3 cells, mainly by inhibiting the TGF-β1/Smad3 signalling pathways. The cellular experiments also indicated that avitinib improved alveolar epithelial cell injury in A549 cells. In conclusion, the present findings demonstrated that avitinib attenuates bleomycin-induced pulmonary fibrosis in mice by inhibiting alveolar epithelial cell injury and myofibroblast activation. [ABSTRACT FROM AUTHOR]

Background Avitinib is one type of the third‐generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of non‐small cell lung cancer (NSCLC) with EGFR mutations. The purpose of this study was to investigate the effect of avitinib on the pharmacokinetics of osimertinib, one FDA approved third‐generation TIKI, both in vitro and in vivo. Methods The in vitro metabolic stability and inhibitory effect of avitinib on osimertinib were assessed with rat liver microsomes (RLM) to determine its IC50 values. For the in vivo study, 18 Sprague‐Dawley rats were randomly divided into three groups: the avitinib multiple dose group (30 mg/kg avitinib once daily for seven days), the avitinib single dose group (PEG200 once daily for six days and a dose of 30 mg/kg avitinib in PEG200 on day 7) and the control group (equal amounts of PEG200 once daily for seven days). Next, all rats were given osimertinib at a dosage of 10 mg/kg. UPLC/MS‐MS was used for the determination of the concentration of osimertinib in plasma. Results In vitro analysis revealed that the IC50 value of osimertinib in rat liver microsomes was 27.6 μM. When rats were pretreated with avitinib, the values of AUC and MRT of the osimertinib were increased, and its Cmax and Tmax were significantly extended, whereas the values of CLz/F were significantly decreased (P

Background: Avitinib is one type of the third‐generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of non‐small cell lung cancer (NSCLC) with EGFR mutations. The purpose of this study was to investigate the effect of avitinib on the pharmacokinetics of osimertinib, one FDA approved third‐generation TIKI, both in vitro and in vivo. Methods: The in vitro metabolic stability and inhibitory effect of avitinib on osimertinib were assessed with rat liver microsomes (RLM) to determine its IC50 values. For the in vivo study, 18 Sprague‐Dawley rats were randomly divided into three groups: the avitinib multiple dose group (30 mg/kg avitinib once daily for seven days), the avitinib single dose group (PEG200 once daily for six days and a dose of 30 mg/kg avitinib in PEG200 on day 7) and the control group (equal amounts of PEG200 once daily for seven days). Next, all rats were given osimertinib at a dosage of 10 mg/kg. UPLC/MS‐MS was used for the determination of the concentration of osimertinib in plasma. Results: In vitro analysis revealed that the IC50 value of osimertinib in rat liver microsomes was 27.6 μM. When rats were pretreated with avitinib, the values of AUC and MRT of the osimertinib were increased, and its Cmax and Tmax were significantly extended, whereas the values of CLz/F were significantly decreased (P < 0.05). Conclusions: Both in vitro and in vivo results demonstrated that a drug‐drug interaction between avitinib and osimertinib occurred and more attention should be paid when avitinib and osimertinib are synchronously administered in clinic. Key points: Significant findings of the study: Osimertinib is the only market available third‐generation EGFR‐TKI and it has been reported that some drugs could have drug‐drug interactions with it. What this study adds: For the first time, we systematically investigated the effect of avitinib, one newly developed third‐generation EGFR‐TKI, on the pharmacokinetics of osimertinib both in vitro and in vivo using a rat model. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Ten reactive metabolites of avitinib were characterized by LC–MS/MS. • Eight in vitro phase I metabolites were detected and their structures were proposed. • Four different bioactivation pathways were identified. • Three nucleophiles were used to capture reactive metabolites. • This study illuminates the way for further work about avitinib toxicity. Abstract Avitinib (AC0010) is a third generation inhibitor of the EGFR (epidermal growth factor receptor) that was permitted parallel phase I clinical trials in the US and in 2014. It is estimated to enter in market within two years. In the current study, eight in vitro metabolites were detected and their chemical structures were postulated. The main in vitro phase-I metabolic reaction was N -oxidation in piperazine moiety. The generation of reactive metabolites in avitinib metabolism was investigated using rat liver microsomes while adding capturing agents, viz potassium cyanide for reactive iminium intermediates, GSH for iminoquinones and methoxylamine for aldehyde forming stable adducts which are identifiable by LC–MS/MS. Ten reactive intermediates (four iminoquinones, three iminium and three aldehydes) were characterized. The three capturing agents used resulted in proposing four different bioactivation pathways. Upon literature examination, no former articles were found for avitinib metabolism including the produced reactive metabolites. [ABSTRACT FROM AUTHOR]

Avitinib (AC0010) is a mutant-selective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), designed to be a targeted therapeutic agent for non-small cell lung cancer (NSCLC) patients harboring EGFR active and T790M resistant mutations. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS) method was developed and validated for the determination of Avitinib and its five metabolites (M1, M2, M4, M7, MII-6) in human cerebrospinal fluid (CSF). The samples were purified by protein precipitation and separated on a BEH C 18 column (2.1 × 50 mm, 1.7 μm). Electrospray ionization (ESI) in positive ion mode and multiple reaction monitoring (MRM) were used to monitor the ion transitions at m / z 488/257, 474/403, 504/487, 434/377, 490/405, 476/391. The results indicated that the method had excellent sensitivity and specificity. The linear range covered from 0.05 to 50 ng/mL for Avitinib, M1, M4, M7, and MII-6, and from 0.01 to 10 ng/mL for M2. Intra-day and inter-day precisions (in terms of% RSD) were all <15% and the accuracies (in terms of% RE) were within the range of ±15%. The lower limit of quantification (LLOQ), matrix effect, extraction recovery, stability and dilution integrity were also validated and satisfied with the criteria of validation. Finally, the method was successfully applied to a blood-brain barrier (BBB) penetration rate research of NSCLC patients after an oral administration of Avitinib. [ABSTRACT FROM AUTHOR]