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
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.