Guglielmi Giorgio, Zamagni Claudio, Del Re Marzia, Danesi Romano, Fogli Stefano
Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
IRCCS Azienda Ospedaliero-universitaria di Bologna, Italy.
Eur J Pharmacol. 2024 Dec 15;985:177076. doi: 10.1016/j.ejphar.2024.177076. Epub 2024 Oct 30.
Understanding the capability of a drug to penetrate the blood-brain barrier (BBB) is an unmet medical need in patients with positive human epidermal growth factor receptor 2 (HER2 positive) and brain metastases. The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib in co-administration with monoclonal antibodies or chemotherapy drugs and the antibody-drug conjugates (ADCs) trastuzumab-deruxtecan and trastuzumab-emtansine. Predicting the BBB permeability of these therapeutic agents is a pharmacological challenge due to the various factors involved in the barrier functions. In this review article, we discuss about the molecular and cellular features of the barriers located in the central nervous system and the pharmacological parameters found to be important in predicting BBB permeability in human normal brain, and in the presence of brain metastases. Finally, we reported the clinical outcomes and intracranial response of patients with HER2-positive breast cancer with brain metastases treated with targeted TKIs and ADCs.
了解药物穿透血脑屏障（BBB）的能力是人类表皮生长因子受体2阳性（HER2阳性）且伴有脑转移的患者尚未满足的医疗需求。美国国立综合癌症网络（NCCN）指南推荐将酪氨酸激酶抑制剂（TKIs）拉帕替尼、奈拉替尼和图卡替尼与单克隆抗体或化疗药物以及抗体药物偶联物（ADCs）曲妥珠单抗-德鲁替康和曲妥珠单抗-恩坦辛联合使用。由于屏障功能涉及多种因素，预测这些治疗药物的血脑屏障通透性是一项药理学挑战。在这篇综述文章中，我们讨论了位于中枢神经系统的屏障的分子和细胞特征，以及在预测人类正常脑和存在脑转移时血脑屏障通透性方面发现的重要药理学参数。最后，我们报告了接受靶向TKIs和ADCs治疗的HER2阳性乳腺癌脑转移患者的临床结局和颅内反应。
