Clinical Pharmacokinetics and Pharmacodynamics of Afatinib

Wind, Sven; Schnell, David; Ebner, Thomas; Freiwald, Matthias; Stopfer, Peter

doi:10.1007/s40262-016-0440-1

Cited by 157 publications

(115 citation statements)

References 53 publications

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“…This issue is addressed in a phase II clinical trial investigating the effect of afatinib on tumor growth in HER2‐positive esophagogastric cancers that do not respond to trastuzumab treatment (Memorial Sloan Kettering Cancer Center ). The broader inhibition profile of afatinib (EGFR, HER2, HER4) compared to trastuzumab (HER2 only) provides the rationale for its use as a therapy in patients with trastuzumab‐resistant tumors (Wind et al ., ). Our in vitro analyses showed an inhibitory effect of afatinib on the activation of AKT1/2/3, WNK1, and ERK1/2 kinases in the HER2‐positive cell line NCI‐N87.…”

Section: Discussionmentioning

confidence: 97%

Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines

et al. 2018

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The molecular mechanism of action of the HER2‐targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream‐acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI‐N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET‐amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor.

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Section: Discussionmentioning

confidence: 97%

Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines

et al. 2018

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“…The lower IC 50 value indicates that afatinib is more potent than first-generation TKIs. Afatinib primarily binds to albumin in the plasma, and its binding ratio is more than 92% in mice and approximately 95% in humans [17][18][19] . Low albumin concentrations in the CSF contribute to unbound afatinib as the primary form.…”

Section: Wwwnaturecom/aps Zhang Sr Et Almentioning

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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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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“…Afatinib (Giotrif®, Boehringer Ingelheim Japan, Tokyo, Japan) is one of the second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), an orally irreversible ErbB family blocker that covalently binds to the kinase domains of EGFR, human EGFRs (HER)2 and 4, and is clinically effective in non-small cell lung cancer (NSCLC) [1].…”

Section: Introductionmentioning

confidence: 99%

Minocycline prevents and repairs the skin disorder associated with afatinib, one of the epidermal growth factor receptor-tyrosine kinase inhibitors for non-small cell lung cancer

2020

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Background: While epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) exert a breakthrough effect, the incidence of skin disorders as a side effect has significantly reduced patients' quality of life. This study aimed to develop a treatment for inflammatory ulcers as one of the side effects of afatinib (Giotrif®), a secondgeneration EGFR-TKI, and established a skin disorder mouse model to investigate the protective effect of minocycline.Methods: First, under inhalation anesthesia with isoflurane, the back of a male ddy mouse was shaved, and afatinib petrolatum was applied alone or in combination with minocycline to observe the state of the skin and measure transepidermal water transpiration (TEWL). Next, afatinib was administered orally to mice, and minocycline petrolatum was applied to observe whether the skin disorder was prevented and its effect on repair of the skin disorder.Results: Skin injury occurred on the back of the mouse following afatinib (1 mg/g in petrolatum) application, and scab formation was observed. Application of minocycline prevented and improved the skin disorder caused by afatinib. When the minocycline-petrolatum mixture was applied to the mouse that developed the skin disorder, a significant improvement in TEWL was observed, and skin repair was observed macroscopically.Conclusions: These results suggest that minocycline petrolatum applied locally prevents and repairs afatinibinduced skin disorders of non-small cell lung cancer patients. Histological examination of skin has provided insights into the mechanism of the occurrence of afatinib-related skin disorder and suggested the efficacy of minocycline topical application in clinical practice.

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Clinical Pharmacokinetics and Pharmacodynamics of Afatinib

Cited by 157 publications

References 53 publications

Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines

Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines

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

Minocycline prevents and repairs the skin disorder associated with afatinib, one of the epidermal growth factor receptor-tyrosine kinase inhibitors for non-small cell lung cancer

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