Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, NY 11439, United States.
Recent Pat Anticancer Drug Discov. 2019;14(2):177-186. doi: 10.2174/1574892814666190212164356.
Computational tools are becoming more and more powerful and comprehensive as compared to past decades in facilitating pharmaceutical, pharmacological and clinical practice. Anticancer agents are used either as monotherapy or in combination therapy to treat malignant conditions of the body. A single antineoplastic agent may be used in different types of malignancies at different doses according to the stage of the disease.
To study the behavior of CPT-11 (Irinotecan) and its metabolite SN-38 in tumor tissue compartment through the Whole Body-Physiologically Pharmacokinetics (WB-PBPK) and to determine the activity of metabolic enzymes and transporters participating in the disposition of CPT-11 and SN-38 working in their physiological environment inside the human body.
Whole body PBPK approach is used to determine the activity of different metabolic enzymes and transporters involved in the disposition of CPT-11 and its active metabolite, SN-38. The concentrations and pharmacokinetic parameters of the parent compound and its metabolite administered at clinically applicable dose via the intravenous route in the tumor tissue are predicted using this approach.
The activity rate constants of metabolic enzymes and transporters of CPT-11 are derived at their natural anatomic locations. Concentration-time curves of CPT-11 and SN-38 with their 5th to 95th percentage range are achieved at the tumor tissue level. Mean tumor tissue pharmacokinetics of both compounds are determined in a population of 100 individuals.
Tumor tissue concentration-time curves of CPT-11 and SN-38 can be determined via PBPK modeling. Rate constants of enzymes and transporters can be shown for healthy and tumor bearing individuals. The results will throw light on the effective concentration of active compound at its target tissue at the clinically applied IV dose.
与过去几十年相比，计算工具在促进药物、药理学和临床实践方面变得越来越强大和全面。抗癌药物要么单独使用，要么联合使用，用于治疗身体的恶性疾病。根据疾病的阶段，单一的抗肿瘤药物可能以不同的剂量用于不同类型的恶性肿瘤。
通过全身体生理药代动力学（WB-PBPK）研究 CPT-11（伊立替康）及其代谢物 SN-38 在肿瘤组织中的行为，并确定参与 CPT-11 和 SN-38 处置的代谢酶和转运体在人体生理环境中的活性，这些酶和转运体在其生理环境中起作用。
全身体 PBPK 方法用于确定参与 CPT-11 及其活性代谢物 SN-38 处置的不同代谢酶和转运体的活性。通过这种方法，预测在临床应用剂量下通过静脉途径在肿瘤组织中给予的母体化合物及其代谢物的浓度和药代动力学参数。
从自然解剖位置得出 CPT-11 的代谢酶和转运体的活性速率常数。在肿瘤组织水平上获得 CPT-11 和 SN-38 的浓度-时间曲线及其 5 至 95 百分位范围。在 100 个人群中确定了两种化合物的平均肿瘤组织药代动力学。
可以通过 PBPK 建模来确定 CPT-11 和 SN-38 的肿瘤组织浓度-时间曲线。可以为健康和肿瘤患者显示酶和转运体的速率常数。结果将阐明在临床应用的 IV 剂量下，活性化合物在其靶组织中的有效浓度。
