title: Cremophor EL pharmacokinetics in a phase I study of paclitaxel (Taxol) and carboplatin in non-small cell lung cancer patients.
abstract: The purpose of our study was to investigate the pharmacokinetics of Cremophor EL following administration of escalating doses of Taxol (paclitaxel dissolved in Cremophor EL/ethanol) to non-small cell lung cancer (NSCLC) patients. Patients with NSCLC stage IIIb or IV without prior chemotherapy treatment were eligible for treatment with paclitaxel and carboplatin in a dose-finding phase I study. The starting dose of paclitaxel was 100 mg/m2 and doses were escalated with steps of 25 mg/m2, which is equal to a starting dose of Cremophor EL of 8.3 ml/m2 with dose increments of 2.1 ml/m2. Carboplatin dosages were 300, 350 or 400 mg/m2. Pharmacokinetic sampling was performed during the first and the second course, and the samples were analyzed using a validated high-performance liquid chromatographic assay. A total of 39 patients were included in this pharmacokinetic part of the study. The doses of paclitaxel were escalated up to 250 mg/m2 (20.8 ml/m2 Cremophor EL). Pharmacokinetic analyses revealed a low elimination-rate of Cremophor EL (CI=37.8-134 ml/h/m2; t 1/2=34.4-61.5 h) and a volume of distribution similar to the volume of the central blood compartment (Vss=4.96-7.85 l). In addition, a dose-independent clearance of Cremophor EL was found indicating linear kinetics. Dose adjustment using the body surface area, however, resulted in a non-linear increase in systemic exposure. The use of body surface area in calculations of Cremophor EL should therefore be re-evaluated.
authors.affiliation: The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam. apjmt@slz.nl
authors.forename: J
authors.initials: J
authors.lastname: Meerum Terwogt
authors.forename: O
authors.initials: O
authors.lastname: van Tellingen
authors.forename: V R
authors.initials: VR
authors.lastname: Nannan Panday
authors.forename: M T
authors.initials: MT
authors.lastname: Huizing
authors.forename: J H
authors.initials: JH
authors.lastname: Schellens
authors.forename: W W
authors.initials: WW
authors.lastname: ten Bokkel Huinink
authors.forename: M U
authors.initials: MU
authors.lastname: Boschma
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
authors.forename: C H
authors.initials: CH
authors.lastname: Veenhof
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D014677:Pharmaceutical Vehicles; C000515:cremophor EL; D016190:Carboplatin; D017239:Paclitaxel; D005990:Glycerol