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Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma
Author(s) -
Lyass Olga,
Uziely Beatrice,
BenYosef Rami,
Tzemach Dinah,
Heshing Norman I.,
Lotem Michal,
Brufman George,
Gabizon Alberto
Publication year - 2000
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(20000901)89:5<1037::aid-cncr13>3.0.co;2-z
Subject(s) - medicine , pharmacokinetics , toxicity , doxorubicin , breast carcinoma , liposome , carcinoma , oncology , metastatic breast cancer , pharmacology , chemotherapy , breast cancer , cancer , materials science , nanotechnology
Abstract BACKGROUND Doxil (ALZA Corp., Mountain View, CA) is a formulation of doxorubicin 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 patients with metastatic breast carcinoma (MBC) previously treated with chemotherapy. 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/m2 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 patients). 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 erythrodysesthesia (PPE) developed usually after two or more courses of treatment and was schedule dependent with shorter dosing intervals leading to increased frequency and severity of skin manifestations. Myelosuppression, mainly as leukopenia/neutropenia, was dose dependent but mild and uncomplicated in 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 observed in only 1 patient who received prior mitoxantrone and mediastinal radiotherapy. Objective responses, improvements, and durable stabilizations were observed in 9, 6, and 14 patients, respectively, indicating significant antitumor activity of Doxil in previously treated MBC patients. Doxil pharmacokinetics 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 concentration) and AUC (area under the concentration*time curve) increased linearly with dose with a statistically significant correlation. Correlation analysis of dose and pharmacokinetic parameters with Doxil toxicites revealed that stomatitis grade and leukocyte nadir were correlated strongly with dose and Cmax, and weakly with AUC, whereas PPE grade was correlated significantly 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 Doxil dosing may be a useful tool. Cancer 2000;89:1037–47. © 2000 American Cancer Society.