title: Population pharmacokinetics of PEGylated liposomal CPT-11 (IHL-305) in patients with advanced solid tumors.
abstract: OBJECTIVE
  To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK.
  
  
  METHODS
  Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was administered as a 1 h IV infusion with doses ranging from 3.5 to 210 mg/m(2). Plasma concentrations of encapsulated CPT-11, released CPT-11 and SN-38 were used to develop a population PK model using NONMEM®.
  
  
  RESULTS
  PK of encapsulated CPT-11 was described by 1-compartment model with nonlinear clearance and PK of released CPT-11 was described by a 1-compartment model with linear clearance for all patients. PK of the active metabolite SN-38 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that gender was a significant covariate for volume of distribution of encapsulated CPT-11. Vencap in male patients is 1.5-fold higher compared with female patients.
  
  
  CONCLUSIONS
  The developed population PK modeling approach is useful to predict PK exposures of encapsulated and released drug and can be applied to the more than 300 other nanoparticle formulations of anticancer agents that are currently in development. The effect of gender on PK of IHL-305 needs to be further evaluated.
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: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Keedy
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Wooin
authors.initials: W
authors.lastname: Lee
authors.forename: Beth A
authors.initials: BA
authors.lastname: Zamboni
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ikeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kodaira
authors.forename: Mace L
authors.initials: ML
authors.lastname: Rothenberg
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D011092:Polyethylene Glycols; D000077146:Irinotecan; D002166:Camptothecin