Reduction of the cardiotoxicity of doxorubicin in rabbits and dogs by encapsulation in long-circulating, pegylated liposomes.
The relative cardiotoxicity of pegylated (STEALTH) liposomal doxorubicin (PL-DOX; Doxil) was compared to nonliposomal doxorubicin (Adriamycin) in rabbits and dogs treated i.v. for up to 22 weeks. No histological evidence of cardiotoxicity was seen in dogs treated with placebo liposomes or PL-DOX every 3 weeks for a total of 10 doses (cumulative doxorubicin dose = 10 mg/kg) either 1 or 5 weeks post-treatment. All dogs treated with the same cumulative dose of free doxorubicin showed marked cardiotoxicity (vacuolization and myofibrillar loss in the myocardium) at both time points. In rabbits, progressive cardiomyopathy was seen in both treatment groups, but was more frequent and severe with free doxorubicin (67% of doxorubicin-treated rabbits, cumulative dose = 12 to 14 mg/kg versus 16% of PL-DOX-treated animals, cumulative dose = 14 to 21 mg/kg). Five doxorubicin-treated rabbits died of congestive heart failure or with histologic evidence of cardiotoxicity (median severity score = 6). No PL-DOX-treated rabbits died of congestive heart failure, although two animals that died early showed microscopic evidence of mild cardiotoxicity (median severity score = 2.5). Cardiotoxicity increased during the post-treatment period in both treatment groups. Rabbits received up to 50% more PL-DOX with no increase in cardiotoxicity. Thus, results in two species demonstrate that the cardiotoxicity of doxorubicin is significantly decreased when administered as PL-DOX. Significantly more PL-DOX can be given without incurring an increased risk of cardiomyopathy. Recent clinical studies have confirmed that PL-DOX is also less cardiotoxic than the same dose of unencapsulated doxorubicin in humans.
Working
P K
PK
SEQUUS Pharmaceuticals, Inc., Menlo Park, California, USA. peter.working@alza.com
Newman
M S
MS
Sullivan
T
T
Yarrington
J
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000633:toxicity*; D004285:Dogs; D004317:Doxorubicin / Q000008:administration & dosage* / Q000633:toxicity*; D004337:Drug Carriers; D004339:Drug Compounding; D005079:Excipients; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology; D008081:Liposomes; D008297:Male; D009206:Myocardium / Q000473:pathology; D011817:Rabbits
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D005079:Excipients; D008081:Liposomes; D004317:Doxorubicin