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Multiple Injections of Pegylated Liposomal Doxorubicin: Pharmacokinetics and Therapeutic Activity
Effects of multiple injections of liposomal doxorubicin on pharmacokinetics, therapeutic outcome, and toxicity were studied in mice using different dosing schedules and dose intensities. Biodistribution of doxorubicin to the cutaneous tissues of mice (skin and paws) and to orthotopically implanted m...
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Published in: | The Journal of pharmacology and experimental therapeutics 2003-09, Vol.306 (3), p.1058-1067 |
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Main Authors: | , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Effects of multiple injections of liposomal doxorubicin on
pharmacokinetics, therapeutic outcome, and toxicity were studied in mice using
different dosing schedules and dose intensities. Biodistribution of
doxorubicin to the cutaneous tissues of mice (skin and paws) and to
orthotopically implanted mammary tumors (4T1) was examined. Weekly intravenous
administration of pegylated (STEALTH) liposomal doxorubicin (SL-DXR) at a dose
of 9 mg/kg (every week à 4 doses) resulted in accumulation of
doxorubicin in cutaneous tissues of mice and development of lesions resembling
palmar-plantar erythrodysesthesia (PPE). Lengthening the dose interval to
every 2 weeks à 4 doses reduced the accumulation of doxorubicin and
lowered the incidence of PPE-like lesions. A dose interval of every 4 weeks
à 4 resulted in complete clearance of doxorubicin from tissues between
subsequent doses and a negligible incidence of PPE-like lesions. Doses of 9
mg/kg SL-DXR given at every week à 2 or every 2 weeks à 2 had
similar therapeutic activities, whereas prolonging the dose interval to every
4 weeks à 2 reduced therapeutic activity. Pharmacokinetics,
biodistribution, and therapeutic activity were studied in tumor-bearing mice
for three dose schedules having the same dose intensity (4.5 mg/kg every 3
days à 4, 9 mg/kg every week à 2, or 18 mg/kg every 2 weeks
à 1). For these schedules, larger doses administered less often tended
to be superior therapeutically to smaller doses given more often. These data
provide the first pharmacokinetic measurements of doxorubicin concentrations
in cutaneous tissues and tumors with repeat administration of liposomal
formulations, and they provide a useful model for the study of factors leading
to PPE in humans. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.103.053413 |