Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma

Citation
O. Lyass et al., Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma, CANCER, 89(5), 2000, pp. 1037-1047
Citations number
36
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER
ISSN journal
0008543X → ACNP
Volume
89
Issue
5
Year of publication
2000
Pages
1037 - 1047
Database
ISI
SICI code
0008-543X(20000901)89:5<1037:COTWPO>2.0.ZU;2-Q
Abstract
BACKGROUND. Doxil (ALZA Corp., Mountain View, CA) is a formulation of doxor ubicin in polyethylene-glycol coated liposomes with a prolonged circulation time and unique toxicity profile. As yet, the effect of the dose schedule on toxicity and the correlation of toxicity with pharmacokinetics have not been directly addressed. METHODS, The objectives of this study were to examine the toxicity profile and pharmacokinetics of various dose schedules of Doxil in a group of patie nts with metastatic breast carcinoma (MBC) previously treated with chemothe rapy. Forty five patients received a total of 268 courses of Doxil (median per patient, 5; range, 1-19). Six dose schedules were investigated: 35 mg/m (2) every 3 weeks (11 patients), 45 mg/m(2) every 3 weeks (5 patients), 50 mg/m(2) every 4 weeks (5 patients), 60 mg/m(2) every 4 weeks (6 patients), 65 mg/m(2) every 5 weeks (6 patients), and 70 mg/m(2) every 6 weeks (12 pat ients). Doxil pharmacokinetics was examined in 24 of these patients at the dose levels of 35, 45, 60, and 70 mg/m(2). RESULTS, Stomatitis was dose related, with higher incidence and severity at doses of 60-70 mg/m(2). Skin toxicity in the form of palmar-plantar erythr odysesthesia (PPE) developed usually after two or more courses of treatment and was schedule dependent with shorter dosing intervals leading to increa sed frequency and severity of skin manifestations. Myelosuppression, mainly as leukopenia/neutropenia, was dose dependent but mild and uncomplicated i n most cases. Hair loss was infrequent (< 7%) and always of limited extent. Despite high cumulative doses up to 1500 mg/m(2), cardiac toxicity was obs erved in only 1 patient who received prior mitoxantrone and mediastinal rad iotherapy. Objective responses, improvements, and durable stabilizations we re observed in 9, 6, and 14 patients, respectively, indicating significant antitumor activity of Doxil in previously treated MBC patients. Doxil pharm acokinetics was well described by a monoexponential elimination curve with a long T-1/2 (median, 79 hours), a slow clearance (median, 40 mL/hour), and a small Volume of distribution (median, 3.9 L). Cmax (peak plasma concentr ation) and AUC (area under the concentration*time curve) increased linearly with dose with a statistically significant correlation. Correlation analys is of dose and pharmacokinetic parameters with Doxil toxicites revealed tha t stomatitis grade and leukocyte nadir were correlated strongly with dose a nd Cmax, and weakly with AUC, whereas PPE grade was correlated significantl y with only 1 parameter, T-1/2. CONCLUSIONS. The toxicity of Doxil is dose and schedule dependent and well correlated with pharmacokinetic parameters. Pharmacokinetic guidance of Dox il dosing may be a useful tool. (C) 2000 American Cancer Society.