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Enzyme and Transporter Kinetics for CPT-11 (Irinotecan) and SN-38: An Insight on Tumor Tissue Compartment Pharmacokinetics Using PBPK

[ Vol. 14 , Issue. 2 ]

Author(s):

Yingfang Fan, Najia Mansoor*, Tasneem Ahmad, Zhuo X. Wu, Rafeeq A. Khan, Martin Czejka, Syed Sharib, Mansoor Ahmed, Zhe S. Chen and Dong H. Yang*   Pages 177 - 186 ( 10 )

Abstract:


Background: 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 anti neoplastic agent may be used in different types of malignancies at different doses according to the stage of the disease.

Objective: 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.

Methods: 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 parent compound and its metabolite administered at clinically applicable dose via intravenous route are predicted using this approach in the tumor tissue.

Results: 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 tumor tissue level. Mean tumor tissue pharmacokinetics of both compounds are determined in a population of 100 individuals

Conclusion: 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.

Keywords:

ADME, CPT -11, neoplasia, pharmacokinetics, SN-38, solid tumors, therapeutic index, whole body-physiology based pharmacokinetics (WB-PBPK).

Affiliation:

Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R, Department of Pharmacology, Faculty of Pharmacy & Pharmaceutical Sciences, University of Karachi, Karachi 75270, Pharma Professional Service, Karachi 75270, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, NY 11439, Department of Pharmacology, Faculty of Pharmacy & Pharmaceutical Sciences, University of Karachi, Karachi 75270, Department of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Pharma Professional Service, Karachi 75270, Department of Pharmaceutical Chemistry, Faculty of Pharmacy & Pharmaceutical Sciences, University of Karachi, Karachi 75270, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, NY 11439, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, NY 11439



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