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 Zamboni11UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, US...
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Dove Medical Press
2012
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oai:doaj.org-article:aabcd19fae254a208e2df1d1184be0832021-12-02T02:06:53ZMechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients1176-91141178-2013https://doaj.org/article/aabcd19fae254a208e2df1d1184be0832012-10-01T00:00:00Zhttp://www.dovepress.com/mechanism-based-model-characterizing-bidirectional-interaction-between-a11319https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Huali 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 kineticsWu HRamanathan RKZamboni BAStrychor SRamalingam SEdwards RPFriedlDMStoller RGBelani CPMaruca LJBang YJZamboni WCDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2012, Iss default, Pp 5555-5564 (2012) |
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Medicine (General) R5-920 Wu H Ramanathan RK Zamboni BA Strychor S Ramalingam S Edwards RP Friedl DM Stoller RG Belani CP Maruca LJ Bang YJ Zamboni WC Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients |
description |
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 |
format |
article |
author |
Wu H Ramanathan RK Zamboni BA Strychor S Ramalingam S Edwards RP Friedl DM Stoller RG Belani CP Maruca LJ Bang YJ Zamboni WC |
author_facet |
Wu H Ramanathan RK Zamboni BA Strychor S Ramalingam S Edwards RP Friedl DM Stoller RG Belani CP Maruca LJ Bang YJ Zamboni WC |
author_sort |
Wu H |
title |
Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients |
title_short |
Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients |
title_full |
Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients |
title_fullStr |
Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients |
title_full_unstemmed |
Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients |
title_sort |
mechanism-based model characterizing bidirectional interaction between pegylated liposomal ckd-602 (s-ckd602) and monocytes in cancer patients |
publisher |
Dove Medical Press |
publishDate |
2012 |
url |
https://doaj.org/article/aabcd19fae254a208e2df1d1184be083 |
work_keys_str_mv |
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