title: Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer.
abstract: The pharmacokinetic behaviour of anticancer drugs may be altered with aging due to (for example) differences in body composition and decreased hepatic and renal function. To address this issue for paclitaxel, we studied the pharmacokinetics of the drug in eight elderly women (>or=70 years) with metastatic breast cancer (median age (range), 77 years (70-84 years)) and a control group of 15 patients aged <70 years (median age (range), 54 years (22-69 years)). Paclitaxel was administered as a 1-h intravenous (i.v.) infusion at a dose of 80 (elderly) or 100 mg/m(2) (<70 years), and serial blood samples were obtained at baseline, and up to 24 h after the end of infusion. Paclitaxel concentration-time profiles were fitted to a linear three-compartment model without any demonstration of saturable behaviour. The clearance of unbound paclitaxel was 124+/-35.0 (elderly) versus 247+/-55.4 l/h/m(2) (<70 years) (P=0.002), and was inversely related to the patient's age (R(2)=0.857; P<0.00001). Total plasma clearance of the formulation vehicle Cremophor EL (CrEL) was 150+/-60.7 (elderly) versus 115+/-39.2 ml/h/m(2) (<70 years) (P=0.04). These data indicate an approximately 50% change in total body clearance of unbound paclitaxel and a concomitant significant increase in systemic exposure with age, most likely as a result of altered CrEL disposition. The clinical relevance of these observations with respect to toxicity profiles and antitumour efficacy requires further evaluation.
authors.affiliation: Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
authors.forename: C H
authors.initials: CH
authors.lastname: Smorenburg
authors.forename: A J
authors.initials: AJ
authors.lastname: ten Tije
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: M
authors.initials: M
authors.lastname: Bontenbal
authors.forename: K
authors.initials: K
authors.lastname: Mross
authors.forename: D M
authors.initials: DM
authors.lastname: van Zomeren
authors.forename: C
authors.initials: C
authors.lastname: Seynaeve
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C022131:cremophor; D011092:Polyethylene Glycols; D017239:Paclitaxel