Pharmacokinetic and pharmacodynamic study of Gefitinib in a mouse model of non-small-cell lung carcinoma with brain metastasis

Chen, Yan; Wang, Mengzhao; Zhong, Wei; Zhao, Jing

doi:10.1016/j.lungcan.2013.08.013

Cited by 43 publications

(37 citation statements)

References 25 publications

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“…The peak penetration rate of afatinib was 4.2% in this study ( Figure 3B). In contrast, the rates are 0.6%-1.3% for gefitinib and 2.8%-4.4% for erlotinib [10,[22][23][24] . A pooled analysis of the results from the LUX-Lung3 and LUX-Lung6 studies by Schuler et al has shown that, compared with chemotherapy, first-line afatinib improves the PFS in EGFR mutation-positive NSCLC patients with BM [5] .…”

Section: Wwwnaturecom/aps Zhang Sr Et Almentioning

confidence: 86%

“…The DAKO EnVision™+ System-HRP was used as the secondary antibody for vitalization, and staining was detected using diaminobenzidine (DAKO). Then, 15 min after streptavidin-peroxidase treatment and washing with TBST, the slides were counterstained with 4',6-diamidino-2-phenylindoleand (DAPI) and visualized by chemiluminescence as described above [10] . To analyze the baseline expression or modulation, IHC scoring of pEGFR was conducted by using the following formula: scoring=0×[% cells with no staining (0)]+1×[% cells with faint to barely visible staining (1+)]+2×[% cells with weak to moderate staining (2+)]+3×[% cells with strong staining (3+)].…”

Section: Immunohistochemistry Analysismentioning

confidence: 99%

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Efficacy of afatinib, an irreversible ErbB family blocker, in the treatment of intracerebral metastases of non-small cell lung cancer in mice

et al. 2016

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Few effective therapeutic options are currently available for the treatment of non-small cell lung cancer (NSCLC) with brain metastases (BM). Recent evidence shows that NSCLC patients with BMs respond well to afatinib, but little is known about the underlying mechanisms. In this study, we evaluated the efficacy of afatinib in treatment of BMs in mice and investigated whether afatinib could actively penetrate the brain-blood barrier and bind to its target. NSCLC BM model was established in nude mice by intracerebral injection of PC-9.luc cells. The tumors were measured weekly using in vivo quantitative bioluminescence. The mice are administrated afatinib (15, 30 mg·kg -1 ·d -1, ig) for 14 d. The antitumor efficacy of afatinib was determined by tumor growth inhibition (TGI), which was calculated as [1-(change of tumor volume in treatment group/control group)×100]. Pharmacokinetic characteristics were measure in mice receiving a single dose of afatinib (30 mg/kg, ig). Pharmacodynamics of afatinib was also assessed by detecting the expression of pEGFR (Tyr1068) in brain tumor foci using immunohistochemistry. Administration of afatinib (15, 30 mg·kg -1 ·d -1 ) dose-dependently inhibited PC-9 tumor growth in the brain with a TGI of 90.2% and 105%, respectively, on d 14. After administration of afatinib (30 mg/kg), the plasma concentration of afatinib was 91.4±31.2 nmol/L at 0.5 h, reached a peak (417.1±119.9 nmol/L) at 1 h, and was still detected after 24 h. The cerebrospinal fluid (CSF) concentrations followed a similar pattern. The T 1/2 values of afatinib in plasma and CSF were 5.0 and 3.7 h, respectively. The AUC (0-24 h) values for plasma and CSF were 2375.5 and 29.1 nmol/h, respectively. The plasma and CSF concentrations were correlated (r=0.844, P<0.01). Pharmacodynamics study showed that the expression levels of pEGFR were reduced by 90% 1 h after afatinib administration. The E max was 86.5%, and the EC 50 was 0.26 nmol/L. A positive correlation between CSF concentrations and pEGFR modulation was revealed. Afatinib penetrates the BBB in NSCLC BM mice and contributes to the brain tumor response. The CSF exposure level is correlated with the plasma level, which in turn is correlated with the modulation of pEGFR in the tumor tissues. The results support for the potential application of afatinib in NSCLC patients with BMs.

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Section: Wwwnaturecom/aps Zhang Sr Et Almentioning

confidence: 86%

Section: Immunohistochemistry Analysismentioning

confidence: 99%

Efficacy of afatinib, an irreversible ErbB family blocker, in the treatment of intracerebral metastases of non-small cell lung cancer in mice

et al. 2016

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“…Available data do not favor one EGFR-TKI over another but the concentration and the penetration in CSF are significantly higher with erlotinib than gefitinib (73)(74)(75). Moreover, P-glycoprotein (P-gp) efflux pump, that is associated with multiple drug resistance in brain tumor, has gefitinib as one of its substrates (76).…”

Section: Cns Penetrationmentioning

confidence: 99%

“…Literature data report that dose escalation, pulsate dose or switching TKIs, seem to improve TKIs concentration in CNS and to relieve resistance to standard TKIs treatment in pts with BM from EGFR mutated NSCLC (70)(71)(72)(73)76,(78)(79)(80)(81)(82)(83) ( Table 1).…”

Section: Alternative Schedulesmentioning

confidence: 99%

“…The greater penetration through the BBB when plasma concentrations are higher, also thanks to P-gp saturation, allows EGFR-TKIs to exert greater activity in CNS (76). However, dose escalation is inevitably related to more frequent and significant side effects including high grade fatigue, nausea and liver damage (70)(71)(72)(73)79,80).…”

Section: Alternative Schedulesmentioning

confidence: 99%

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Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future

Proto¹,

Imbimbo²,

Gallucci³

et al. 2016

Transl. Lung Cancer Res.

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A validated high‐performance liquid chromatography–tandem mass spectrometry method for quantification of gefitinib and its main metabolites in xenograft mouse tumor: Application to a pharmacokinetics study

Zhao

Zheng

Yang

et al. 2019

Biomedical Chromatography

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Monitoring gefitinib and its metabolites may help to explore the underlying mechanisms of gefitinib resistance. The concentration of gefitinib and its metabolites in tumor tissues could influence its anticancer activities more than that in the plasma. In the present study, a rapid and specific HPLC–MS/MS method was developed and validated to simultaneously determine gefitinib, M387783, M523595, M537194 and M608236 in tumor tissues of H1975 human lung cancer xenografts of nude mice. The established HPLC–MS/MS method was validated for specificity, linearity, accuracy and precision, matrix effect and recovery, carryover and dilution integrity, and analyte stability. The standard curves were linear (r2 ≥ 0.99) over the range of 0.5–100 ng/mL for M608236 and 1–200 ng/mL for gefitinib, M523595 and M537194 as well as M387783. The accuracy ranged from −8.35 to 6.03% relative error; and the precision was <15% relative standard deviation. Recoveries (87.74–99.96%) and matrix effects (86.60–106.40%) were satisfactory in the biological matrix examined. Stability studies showed that the analytes were stable during the assay procedure and storage. Finally, the validated method was successfully applied to study the pharmacokinetics profiles for gefitinib and its metabolites in nonsmall cell lung cancer (NSCLC) xenograft mouse tumors. Meanwhile, MTT assay showed that gefitinib had a more powerful inhibitory effect than its four major metabolites in H1975 NSCLC cells. This validated HPLC–MS/MS method may be applied to help understand the mechanisms of gefitinib resistance in EGFR‐mutant nonsmall cell lung cancer.

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Pharmacokinetic and pharmacodynamic study of Gefitinib in a mouse model of non-small-cell lung carcinoma with brain metastasis

Cited by 43 publications

References 25 publications

Efficacy of afatinib, an irreversible ErbB family blocker, in the treatment of intracerebral metastases of non-small cell lung cancer in mice

Efficacy of afatinib, an irreversible ErbB family blocker, in the treatment of intracerebral metastases of non-small cell lung cancer in mice

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future

A validated high‐performance liquid chromatography–tandem mass spectrometry method for quantification of gefitinib and its main metabolites in xenograft mouse tumor: Application to a pharmacokinetics study

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