Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients
| Autor: | Wu H, Ramanathan RK, Zamboni BA, Strychor S, Ramalingam S, Edwards RP, Friedl, DM, Stoller RG, Belani CP, Maruca LJ, Bang YJ, Zamboni WC |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | International Journal of Nanomedicine, Vol 2012, Iss default, Pp 5555-5564 (2012) |
| Druh dokumentu: | article |
| ISSN: | 1176-9114 1178-2013 |
| Popis: | 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 Zamboni11UNC 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, KoreaAbstract: 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 |
| Databáze: | Directory of Open Access Journals |
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