Fan Yingfang, Mansoor Najia, Ahmad Tasneem, Khan Rafeeq Alam, Czejka Martin, Sharib Syed, Yang Dong-Hua, Ahmed Mansoor
Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
Department Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Oncotarget. 2017 Jul 18;8(29):48178-48185. doi: 10.18632/oncotarget.18380.
Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Treatment of colorectal cancer remains a challenge to clinicians as well as drug developers. Irinotecan, a Camptothecin derivative, is successfully used for the treatment of this rapidly progressing malignancy and finds its place in the first line of therapeutic agents. Irinotecan is also effective in treating SCLC, malignant glioma and pancreatic adenocarcinoma. However, its adverse effects limit its clinical application. Mainly metabolized by hepatic route, and excreted through biliary tract, this dug has been found to possess high variation in patients in its pharmacokinetic (PK) profile. Physiologically based pharmacokinetic (PBPK) models using compartmental approach have attained their position to foresee the possible PK behavior of different drugs before their administration to patients and such models have been proposed for several anticancer agents. In this work, we used WB-PBPK technology to develop a model in a population of tumor patients who used IV irinotecan therapy. This model depicted the concentration of drug and its pharmacologically active metabolite in human body over a specific period of time. Knowledge about pharmacokinetic parameters is extracted from this profile and the model is evaluated by the observed results of clinical study presented in literature. The predicted behavior of the drug by this approach is in good agreement with the observed results and can aid in further exploration of PK of irinotecan in cancer patients, especially in those concomitantly suffer from other morbidity.
结直肠癌是美国癌症相关死亡的第三大主要原因。结直肠癌的治疗对临床医生和药物研发人员来说仍然是一项挑战。伊立替康，一种喜树碱衍生物，已成功用于治疗这种快速进展的恶性肿瘤，并在一线治疗药物中占有一席之地。伊立替康在治疗小细胞肺癌、恶性胶质瘤和胰腺腺癌方面也很有效。然而，其副作用限制了它的临床应用。这种药物主要通过肝脏途径代谢，并通过胆道排泄，已发现其在患者体内的药代动力学（PK）特征存在很大差异。使用房室方法的基于生理的药代动力学（PBPK）模型已能够在不同药物给患者使用之前预测其可能的PK行为，并且已经针对几种抗癌药物提出了这样的模型。在这项工作中，我们使用WB-PBPK技术在接受静脉注射伊立替康治疗的肿瘤患者群体中开发了一个模型。该模型描绘了特定时间段内药物及其药理活性代谢物在人体内的浓度。从该曲线中提取有关药代动力学参数的知识，并通过文献中呈现的临床研究观察结果对模型进行评估。通过这种方法预测的药物行为与观察结果高度一致，并且有助于进一步探索伊立替康在癌症患者中的PK，特别是在那些同时患有其他疾病的患者中。
