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Theoretical method for evaluation of therapeutic effects and adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors in clinical treatment

机译：表皮生长因子受体酪氨酸激酶抑制剂在临床治疗中评价的理论方法

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Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for non-small cell lung cancer patients with an EGFR gene mutation. However, skin disorders are known as adverse events. In the present study, we investigated whether EGFR-TK occupancy is useful as an index for assessing clinical efficacy and adverse events for the proper use and development of EGFR-TKIs. Average binding occupancies (Phi(ss)) of EGFR-TKIs, gefitinib and erlotinib, for the EGFR-TK of cancer or skin cells were calculated. The relationships of Uss with response rate (RR) or frequency of rash were analyzed using the ternary complex model. Then, the relationships between the dose of EGFR-TKIs and RR or frequency of rash were examined. Gefitinib showed a greater difference for Phi(ss) value for both wild-type and mutant EGFR as compared to erlotinib at usual dose. The RR increased in a nonlinear manner rapidly rising when Phi(ss) exceeded 95%. It was thought that a very high Uss value might be needed to obtain the therapeutic effect of EGFR-TKIs. Meanwhile, the frequency of rash increased in a linear manner along with elevation of Phi(ss). It was shown that the K-d ratio (K-d for mutant/K-d for wild type) was less than 0.001, when the high RR and low frequency of rash were obtained simultaneously. The results showed that the therapeutic effects and skin disorder can be assessed by using Phi(ss). Furthermore, it is likely that a proper choice of drug and dose can be made by using Phi(ss) in EGFR-TKI therapy.
机译：表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIS）用于非小细胞肺癌患者EGFR基因突变。然而，皮肤病被称为不良事件。在本研究中，我们研究了EGFR-TK占用率是否可​​用作评估临床疗效和不良事件的指数，以适当使用和开发EGFR-TKIS。计算EGFR-TKI，GEFITINIB和ERLOTINIB的平均结合占用（PHI（SS）），用于癌症或皮肤细胞的EGFR-TK。使用三元复杂模型分析了USS对响应速率（RR）或皮疹频率的关系。然后，检查EGFR-TKIS和RR的剂量与皮疹的频率之间的关系。与常规剂量相比，吉替尼对野生型和突变蛋白EGFR的PHI（SS）值差异更大。当PHI（SS）超过95％时，RR以非线性方式的不断增加增加。据认为，可能需要非常高的USS值来获得EGFR-TKI的治疗效果。同时，皮疹的频率以线性方式和phi（ss）的升高增加。结果表明，当同时获得高RR和高频的皮疹频率时，K-D比（用于野生型的突变体/ k-d的K-D）小于0.001。结果表明，通过使用PHI（SS）可以评估治疗效果和皮肤疾病。 Furthermore, it is likely that a proper choice of drug and dose can be made by using Phi(ss) in EGFR-TKI therapy.

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