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

Authors Wu H, Ramanathan RK, Zamboni BA, Strychor S, Ramalingam S, Edwards RP, Friedland DM, Stoller RG, Belani CP, Maruca LJ, Bang YJ, Zamboni WC

Received 9 July 2012

Accepted for publication 17 August 2012

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

DOI https://doi.org/10.2147/IJN.S35751

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

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