Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies

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

17 Scopus citations

Abstract

S-CKD602 is a pegylated long-circulating liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. A population pharmacokinetic (PK) model for encapsulated and released CKD-602 following administration of S-CKD602 was developed to assess factors that may influence S-CKD602 PK. Plasma samples from 45 patients with solid tumors were collected in a phase 1 study. S-CKD602 was administered as a 1-hour intravenous infusion with doses ranging from 0.1 to 2.5 mg/m2. Plasma concentrations of encapsulated and released CKD-602 were used to develop a population PK model using NONMEM. PK of encapsulated CKD-602 was described by a 1-compartment model with nonlinear clearance, and PK of released CKD-602 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that tumor in the liver was a significant covariate for clearance of encapsulated CKD-602 and that age significantly influenced the release rate of CKD-602 from S-CKD602. Maximum elimination rate in patients with liver tumor is 1.5-fold higher compared with patients without liver tumor. Release rate of CKD-602 from S-CKD602 in patients less than 60 years old was 2.7-fold higher compared with patients 60 years old or older. These observations have potential implications in the optimal dosing of liposomal agents.

Original languageEnglish (US)
Pages (from-to)180-194
Number of pages15
JournalJournal of Clinical Pharmacology
Volume52
Issue number2
DOIs
StatePublished - Feb 2012

Keywords

  • S-CKD602
  • liver metastasis
  • nonlinear kinetics
  • pegylated liposome
  • population pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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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). Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies. Journal of Clinical Pharmacology, 52(2), 180-194. https://doi.org/10.1177/0091270010394851