title: Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients.
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.
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
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: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003198:Computer Simulation; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes / Q000737:chemistry*; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry*; D014018:Tissue Distribution; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D059004:Topoisomerase I Inhibitors; C116963:belotecan; D011092:Polyethylene Glycols; D002166:Camptothecin
keywords: PEGylated liposome; nonlinear kinetics; pharmacodynamics; population pharmacokinetics