Back to Journals » International Journal of Nanomedicine » Volume 7

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

Authors Wu H, Ramanathan R, Zamboni B, Strychor, Ramalingam, Edwards R, Friedland, Stoller, Belani C, Maruca, Bang Y, Zamboni W

Received 9 July 2012

Accepted for publication 17 August 2012

Published 19 October 2012 Volume 2012:7 Pages 5555—5564


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Huali Wu,1 Ramesh K Ramanathan,2 Beth A Zamboni,3 Sandra Strychor,4 Suresh Ramalingam,5 Robert P Edwards,4 David M Friedland,4 Ronald G Stoller,4 Chandra P Belani,4 Lauren J Maruca,4 Yung-Jue Bang,6 William C Zamboni1

1UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA; 2Translational Research Division, The Translational Genomics Research Institute, Scottsdale, AZ, USA; 3Department of Mathematics, Carlow University, Pittsburgh, PA, USA; 4School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; 5Winship Cancer Institute, Emory University, Atlanta, GA, USA; 6College of Medicine, Seoul National University, Seoul, Korea

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.

Keywords: population pharmacokinetics, pharmacodynamics, PEGylated liposome, nonlinear kinetics

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]


Other article by this author:

Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors

Wu H, Infante JR, Keedy VL, Jones SF, Chan E, Bendell JC, Lee W, Kirschbrown WP, Zamboni BA, Ikeda S, Kodaira H, Rothenberg ML, Burris III HA, Zamboni WC

International Journal of Nanomedicine 2015, 10:1201-1209

Published Date: 10 February 2015

Readers of this article also read:

An optimized molecular inclusion complex of diferuloylmethane: enhanced physical properties and biological activity

Tan Q, Li Y, Wu J, Mei H, Zhao C, Zhang J

International Journal of Nanomedicine 2012, 7:5385-5393

Published Date: 9 October 2012

Preparation and evaluation of SiO2-deposited stearic acid-g-chitosan nanoparticles for doxorubicin delivery

Yuan H, Bao X, Du YZ, You J, Hu FQ

International Journal of Nanomedicine 2012, 7:5119-5128

Published Date: 26 September 2012

Biocompatibility of magnetic Fe3O4 nanoparticles and their cytotoxic effect on MCF-7 cells

Chen DZ, Tang QS, Li XD, Zhou XJ, Zang J, Xue WQ, Xiang JY, Guo CQ

International Journal of Nanomedicine 2012, 7:4973-4982

Published Date: 14 September 2012

Indomethacin-loaded lipid-core nanocapsules reduce the damage triggered by Aβ1-42 in Alzheimer’s disease models

Bernardi A, Frozza RL, Meneghetti A, Hoppe JB, Battastini AMO, Pohlmann AR, Guterres SS, Salbego CG

International Journal of Nanomedicine 2012, 7:4927-4942

Published Date: 13 September 2012

In vitro and in vivo studies of surface-structured implants for bone formation

Xia L, Feng B, Wang PZ, Ding SY, Liu ZY, Zhou J, Yu R

International Journal of Nanomedicine 2012, 7:4873-4881

Published Date: 11 September 2012

Nanoparticles and their potential for application in bone

Tautzenberger A, Kovtun A, Ignatius A

International Journal of Nanomedicine 2012, 7:4545-4557

Published Date: 17 August 2012

Nanoinformatics: a new area of research in nanomedicine

Maojo V, Fritts M, de la Iglesia D, Cachau RE, Garcia-Remesal M, Mitchell JA, Kulikowski C

International Journal of Nanomedicine 2012, 7:3867-3890

Published Date: 24 July 2012

Improved biological properties and hypouricemic effects of uricase from Candida utilis loaded in novel alkaline enzymosomes

Tan QY, Zhang JQ, Wang N, Yang H, Li X, Xiong HR, Wu JY, Zhao CJ, Wang H, Yin HF

International Journal of Nanomedicine 2012, 7:3929-3938

Published Date: 23 July 2012

Nimodipine-loaded mixed micelles: formulation, compatibility, pharmacokinetics, and vascular irritability study

Song X, Jiang Y, Ren CJ, Sun X, Zhang Q, Gong T, Zhang ZR

International Journal of Nanomedicine 2012, 7:3689-3699

Published Date: 13 July 2012

Acoustic cardiac signals analysis: a Kalman filter–based approach

Salleh SH, Hussain HS, Swee TT, Ting CM, Noor AM, Pipatsart S, Ali J, Yupapin PP

International Journal of Nanomedicine 2012, 7:2873-2881

Published Date: 11 June 2012