title: Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors.
abstract: IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes.
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Huali
authors.initials: H
authors.lastname: Wu
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Vanderbilt University, Nashville, TN, USA.
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Keedy
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, USA.
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.affiliation: Vanderbilt University, Nashville, TN, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, USA.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.
authors.forename: Wooin
authors.initials: W
authors.lastname: Lee
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Whitney P
authors.initials: WP
authors.lastname: Kirschbrown
authors.affiliation: Department of Mathematics, Carlow University, Pittsburgh, PA, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Zamboni
authors.affiliation: Yakult Honsha Co., Ltd., Medical Development Department, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Yakult Honsha Co., Ltd., Medical Development Department, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kodaira
authors.affiliation: Vanderbilt University, Nashville, TN, USA.
authors.forename: Mace L
authors.initials: ML
authors.lastname: Rothenberg
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA ; UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA ; UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA ; Carolina Center for Cancer Nanotechology Excellence, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008081:Liposomes / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D011092:Polyethylene Glycols; D000077146:Irinotecan; D002166:Camptothecin
keywords: CPT-11; IHL-305; PEGylated liposome; irinotecan; monocytes; pharmacokinetics