The pharmacokinetics of a 1-h paclitaxel infusion.
OBJECTIVE
To characterize the disposition of paclitaxel (PAC) after a 1-h infusion in humans and define if possible a pharmacodynamic relationship between PAC disposition and the observed toxicity.


METHODS
PAC pharmacokinetics were studied in 43 courses of therapy in 30 patients (30 first course, 13 PK third course). PAC was administered at 150, 175, 200, 225 and 250 mg/m2 by a 1-h infusion to patients with advanced cancer (lung, breast, ovarian, cervix, and head and neck). PAC was quantified by high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were calculated by noncompartmental and model-dependent methods.


RESULTS
Increases in the area under the curve and the peak plasma concentration were not proportional to increases in the dose. However, the deviation from linearity is rather moderate. The dose-limiting toxicity was central neuropathy which was not associated with pharmacokinetic deviations. Owing to the absence of grade 3 or 4 myelotoxicity, no clear correlation between this toxicity and pharmacokinetic parameters could be established.


CONCLUSIONS
Within the evaluated dose range of the 1-h infusion there was only a moderate nonlinear disposition of PAC in humans and therefore a dose of 225 mg/m2 is recommended as safe. The observation of central neuropathy could not be directly related to a pharmacokinetic parameter. The complexity of the formulation which included Cremophor EL and ethanol may offer an explanation for the observed central neurotoxicity.
Mross
K
K
Department of Medical Oncology and Clinical Pharmacology, Tumor Biology Center at the Albert-Ludwigs-University Freiburg, Germany. mross@tumorbio.uni-freiburg.de
Holländer
N
N
Hauns
B
B
Schumacher
M
M
Maier-Lenz
H
H
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000378:metabolism; D004341:Drug Evaluation; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014594:Uterine Neoplasms / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel