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

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 Zamboni<sup>1

1</sup>UNC 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

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php 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.