Abstract
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 × 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 × 4 doses reduced the accumulation of doxorubicin and lowered the incidence of PPE-like lesions. A dose interval of every 4 weeks × 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 × 2 or every 2 weeks × 2 had similar therapeutic activities, whereas prolonging the dose interval to every 4 weeks × 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 × 4, 9 mg/kg every week × 2, or 18 mg/kg every 2 weeks × 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.
Footnotes
-
This research was supported by the Canadian Institutes of Health Research (UOP 48092) and ALZA Corporation (Mountain View, CA). Gregory Charrois is the recipient of a graduate studentship from the Alberta Heritage Foundation for Medical Research.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
DOI: 10.1124/jpet.103.053413.
-
ABBREVIATIONS: SL-DXR, pegylated (STEALTH) liposomal doxorubicin (Doxil/Caelyx); PPE, palmar-plantar erythrodysesthesia; D5W, dextrose 5% in sterile water; q, every; AUC, area under the plasma/tissue concentration versus time curve; MPS, mononuclear phagocyte system.
- Received April 24, 2003.
- Accepted June 5, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|