Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors

• Published in: International journal of nanomedicine Vol. 10; no. default; pp. 1201 - 1209
• Main Authors: Wu, Huali, Infante, Jeffrey R, Keedy, Vicki L, Jones, Suzanne F, Chan, Emily, Bendell, Johanna C, Lee, Wooin, Kirschbrown, Whitney P, Zamboni, Beth A, Ikeda, Satoshi, Kodaira, Hiroshi, Rothenberg, Mace L, Burris, 3rd, Howard A, Zamboni, William C
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Press 01.01.2015; Dove Medical Press
• Subjects: Adult; Aged; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Camptothecin - analogs & derivatives; Camptothecin - blood; Camptothecin - pharmacokinetics; Camptothecin - pharmacology; Camptothecin - therapeutic use; CPT-11; Female; Humans; IHL-305; Irinotecan; Liposomes - blood; Liposomes - pharmacokinetics; Liposomes - pharmacology; Liposomes - therapeutic use; Male; Middle Aged; monocytes; Neoplasms - drug therapy; Original Research; PEGylated liposome; pharmacokinetics; Polyethylene Glycols - analysis; Polyethylene Glycols - pharmacokinetics; Polyethylene Glycols - pharmacology; Polyethylene Glycols - therapeutic use; IHL-305; pharmacokinetics; monocytes; irinotecan; CPT-11; PEGylated liposome
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S62911

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.