title: Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies.
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/m(2) . 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.
authors.affiliation: University of North Carolina (UNC) Eshelman School of Pharmacy, UNC, Chapel Hill, North CarolinaUNC Lineberger Comprehensive Cancer Center, UNC, Chapel Hill, North CarolinaUNC Institute for Pharmacogenomics and Individualized Therapy, UNC, Chapel Hill, North CarolinaCarolina Center for Cancer Nanotechology Excellence, UNC, Chapel Hill, North CarolinaUniversity of Pittsburgh Cancer Institute, Pittsburgh, PennsylvaniaSchool of Medicine, University of Pittsburgh, PittsburghDepartment of Mathematics, Carlow University, PittsburghCKD Research Institute, Chonan, KoreaSeoul National University Hospital, Seoul, Korea.
authors.forename: Huali
authors.initials: H
authors.lastname: Wu
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Beth A
authors.initials: BA
authors.lastname: Zamboni
authors.forename: Sandra
authors.initials: S
authors.lastname: Strychor
authors.forename: Suresh
authors.initials: S
authors.lastname: Ramalingam
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.forename: David M
authors.initials: DM
authors.lastname: Friedland
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Stoller
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Maruca
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
mesh_terms: D000328:Adult; D000368:Aged; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D008081:Liposomes; D059004:Topoisomerase I Inhibitors; C116963:belotecan; D011092:Polyethylene Glycols; D002166:Camptothecin