title: Influence of dose and animal species on accelerated blood clearance of PEGylated liposomal doxorubicin.
abstract: We recently demonstrated that Doxil loses its long-circulating properties when injected repeatedly at doses below 2 mg/m(2) in dogs. In studies using other animal species, PEGylated liposomal doxorubicin has been reported not to induce the accelerated blood clearance (ABC) phenomenon. We investigated the issue of whether Doxil can elicit the ABC phenomenon in several species. In minipigs, the ABC phenomenon was induced at 2 mg/m(2). In other animal species, the ABC phenomenon was not observed at higher doses (>2 mg/m(2)), but was observed at much lower doses (0.2 mg/m(2)). The pharmacokinetic profile of a second dose of Doxil reflected the circulating anti-PEG IgM level induced by the first dose. The ABC phenomenon was not observed at the clinically recommended DXR dose (20 mg/m(2)) in any animal species. These results indicate that Doxil can cause the ABC phenomenon in all animals tested, the extent of induction was dependent on the first dose of Doxil, and a higher Doxil dose lessened the ABC phenomenon. The current study results suggest that a careful study design including selection of animal species is important for preclinical studies using PEGylated liposomal formulations even if they contain anticancer drugs that suppress the host immune response.
authors.affiliation: DDS Research, Global Formulation Research Japan, Pharmaceutical Science and Technology, Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Electronic address: t25-suzuki@hhc.eisai.co.jp.
authors.forename: Takuya
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima; 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Ichihara
authors.affiliation: DDS Research, Global Formulation Research Japan, Pharmaceutical Science and Technology, Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hyodo
authors.affiliation: DDS Research, Global Formulation Research Japan, Pharmaceutical Science and Technology, Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Yamamoto
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima; 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima; 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
authors.affiliation: Formulation Strategy, Global Formulation Research, Pharmaceutical Science and Technology, Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: DDS Research, Global Formulation Research Japan, Pharmaceutical Science and Technology, Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishihara
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007075:Immunoglobulin M / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature
chemical_list: D000903:Antibiotics, Antineoplastic; D007075:Immunoglobulin M; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Accelerated blood clearance phenomenon; Doxil; Doxorubicin; PEGylated liposomes; Polyethylene glycol; Species difference