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

Huali Wu, Ramesh K. Ramanathan, Beth A. Zamboni, Sandra Strychor, Suresh Ramalingam, Robert P. Edwards, David M. Friedland, Ronald G. Stoller, Chandra P. Belani, Lauren J. Maruca, Yung Jue Bang, William C. Zamboni

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5555-5564
Number of pages10
JournalInternational journal of nanomedicine
Volume7
DOIs
StatePublished - 2012

Keywords

  • Nonlinear kinetics
  • PEGylated liposome
  • Pharmacodynamics
  • Population pharmacokinetics

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Biomaterials
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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    Wu, H., Ramanathan, R. K., Zamboni, B. A., Strychor, S., Ramalingam, S., Edwards, R. P., Friedland, D. M., Stoller, R. G., Belani, C. P., Maruca, L. J., Bang, Y. J., & Zamboni, W. C. (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. https://doi.org/10.2147/IJN.S35751