Accelerated blood clearance of pegylated liposomal topotecan: influence of polyethylene glycol grafting density and animal species.
Upon repeated administration, empty pegylated liposomes lose long-circulating characteristics, referred to as accelerated blood clearance (ABC) phenomenon. However, pegylated liposomal cytotoxic drug formulations could not elicit the phenomenon. In the study, it was found that repeated injection of pegylated liposomal topotecan could induce ABC phenomenon in Wistar rats, beagle dogs, and mice, which might be associated with the formation of empty liposomes in circulation because of the rapid drug release rate. In rats, the 9% polyethylene glycol (PEG) formulation induced more severe ABC phenomenon than 3% PEG formulation despite the similar anti-PEG immunoglobulin M (IgM) levels following the first dose. Antibody neutralization experiments revealed that high PEG formulation was easily neutralized by IgM. Repeated administration of 3% PEG formulation in dogs could result in more severe ABC phenomenon. It seems that slow infusion was liable to cause ABC phenomenon. In all animal species, considerable intraindividual variability of IgM levels could be observed. Our observations may have important implications for the development, evaluation, and therapeutic use of pegylated liposomal cytotoxic drug formulations because using the current drug loading technology, most of the cytotoxic drugs could not be stably loaded in liposomes and rapid drug leakage from liposomes might occur in circulation.
CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Company, Ltd., Shijiazhuang, China. lcllib@hotmail.com
Chunlei
C
Li
Jinna
J
Cao
Yajuan
Y
Wang
Xi
X
Zhao
Chenxin
C
Deng
Na
N
Wei
Jian
J
Yang
Jingxia
J
Cui
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004285:Dogs; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry; D005260:Female; D007075:Immunoglobulin M / Q000097:blood; D008081:Liposomes / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D019772:Topotecan / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry* / Q000493:pharmacokinetics
D007075:Immunoglobulin M; D008081:Liposomes; D011092:Polyethylene Glycols; D019772:Topotecan; D004317:Doxorubicin