Physiologically based pharmacokinetic modeling for predicting irinotecan exposure in human body
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Yingfang Fan1,2,*, Najia Mansoor3,*, Tasneem Ahmad4, Rafeeq Alam Khan3, Martin Czejka5, Syed Sharib4, Dong-Hua Yang2 and Mansoor Ahmed6
1Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
2Department Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
3Department of Pharmacology, Faculty of Pharmacy & Pharmaceutical Sciences, University of Karachi, Karachi 75270, Pakistan
4Pharma Professional Services, Karachi 75270, Pakistan
5Department of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Austria
6Department of Pharmaceutical Chemistry, Faculty of Pharmacy & Pharmaceutical Sciences, University of Karachi, Karachi 75270, Pakistan
*These authors have contributed equally to this work
Mansoor Ahmed, email: [email protected]
Dong-Hua Yang, email: [email protected]
Keywords: physiologically based pharmacokinetics (PBPK), irinotecan, colorectal cancer
Received: March 24, 2017 Accepted: May 04, 2017 Published: June 06, 2017
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.
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