Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients

• Type of Material: Article
• Authors: Huali Wu, University of North Carolina; Ramesh K. Ramanathan, The Translational Genomics Research Institute; Beth A. Zamboni, Carlow University; Sandra Strychor, University of Pittsburgh; Suresh Ramalingam, Emory University; Robert P. Edwards, University of Pittsburgh; David M. Friedland, University of Pittsburgh; Ronald G. Stoller, University of Pittsburgh; Chandra P. Belani, University of Pittsburgh; Lauren J. Maruca, University of Pittsburgh; Yung-Jue Bang, Seoul National University; William C. Zamboni, University of North Carolina
• Language: English
• Date: 2012-10-18
• Publisher: Dove Medical Press
• Publication Version: Final Published Version
• Copyright Statement: © 2012 Wu et al, publisher and licensee Dove Medical Press Ltd.
• Final Published Version (URL): http://dx.doi.org/10.2147/IJN.S35751
• Title of Journal or Parent Work: International Journal of Nanomedicine
• ISSN: 1176-9114
• Volume: 7
• Start Page: 5555
• End Page: 5564
• Grant/Funding Information: This work was supported by ALZA, Mountain View, CA and NIH/NCCR/GCRC grant 5M01 RR 00056.
• Keywords: PEGylated liposome; Life Sciences & Biomedicine; PHARMACOLOGY & PHARMACY; DRUGS; TIME-COURSE; Pharmacology & Pharmacy; ADVANCED MALIGNANCIES; population pharmacokinetics; PHASE-I; Science & Technology - Other Topics; PHARMACODYNAMIC MODEL; CHEMOTHERAPY; NEUTROPENIA; PHARMACOKINETIC PARAMETERS; nonlinear kinetics; LUNG-CANCER; Science & Technology; pharmacodynamics; NANOSCIENCE & NANOTECHNOLOGY; ANTICANCER AGENTS; Nanoscience & Nanotechnology
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic-pharmacodynamic (PK-PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK-PD models were developed and fit simultaneously to the PK-PD data, using NONMEM®. The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis-Menten kinetics in the myelosuppression-based model. The mechanism-based PK-PD model characterized the nonlinear PK disposition, and the bidirectional PK-PD interaction between S-CKD602 and monocytes. © 2012 Cárdenas et al, publisher and licensee Dove Medical Press Ltd.