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Int J Nanomedicine. 2012;7:5555-64. doi: 10.2147/IJN.S35751. Epub 2012 Oct 19.

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

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1
UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.

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:

PEGylated liposome; nonlinear kinetics; pharmacodynamics; population pharmacokinetics

PMID:
23112576
PMCID:
PMC3480239
DOI:
10.2147/IJN.S35751
[Indexed for MEDLINE]
Free PMC Article
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