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

Wu, H and Ramanathan, RK and Zamboni, BA and Strychor, S and Ramalingam, S and Edwards, RP and Friedland, DM and Stoller, RG and Belani, CP and Maruca, LJ and Bang, YJ and Zamboni, WC (2012) Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients. International Journal of Nanomedicine, 7. 5555 - 5564. ISSN 1176-9114

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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.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wu, H
Ramanathan, RK
Zamboni, BA
Strychor, S
Ramalingam, S
Edwards, RPrpe1@pitt.eduRPE10000-0003-0370-1390
Friedland, DM
Stoller, RG
Belani, CP
Maruca, LJ
Bang, YJ
Zamboni, WC
Date: 5 December 2012
Date Type: Publication
Journal or Publication Title: International Journal of Nanomedicine
Volume: 7
Page Range: 5555 - 5564
DOI or Unique Handle: 10.2147/ijn.s35751
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
ISSN: 1176-9114
Date Deposited: 03 Dec 2012 22:26
Last Modified: 22 Apr 2024 17:55
URI: http://d-scholarship.pitt.edu/id/eprint/16703

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