title: Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre.
abstract: OBJECTIVE
  To investigate the pharmacokinetics and pharmacodynamics of paclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escalating study in untreated non-small-cell lung cancer (NSCLC) patients.
  
  
  METHODS
  Fifty-five chemotherapy-naive patients with NSCLC were entered onto the pharmacokinetic part of a large phase I trial in which P was administered as a 3-hour infusion at dosages of 100 to 250 mg/m2, and C over 30 minutes at dosages of 300 to 400 mg/m2. Patients were randomized for the sequence of administration, first C followed by P or vice versa. Each patient received the alternate sequence during the second and subsequent courses.
  
  
  RESULTS
  The most important hematologic toxicity encountered-was neutropenia. Hematologic toxicity was not dependent on the sequence in which P and C were administered, but there was cumulative neutropenia. Nonhematologic toxicities consisted mainly of vomiting, myalgia, and arthralgia. No sequence-dependent pharmacokinetic interactions for the P area under the concentration-time curve (P-AUC), maximal plasma concentration (P-Cmax), or time above a threshold concentration of 0.1 mumol/L (P-T > or = 0.1 mumol/L) were observed. However, there was a significant difference for the metabolite 6 alpha-hydroxypaclitaxel AUC (6OHP-AUC). Higher 6OHP-AUCs were observed when C was administered before P. The mean plasma ultrafiltrate AUC of C (CpUF-AUC) at the dosage of 300 mg/m2 for the sequence C-->P was 3.52 mg/mL.min (range, 1.94 to 5.83) and 3.62 mg/mL.min for the sequence P-->C (range, 1.91 to 5.01), which is not significantly different (P = .55). Of 45 assessable patients, there were five major responders (three complete responders and two partial responders). Four of five responses occurred at dosages above dose level 4 (P 175 mg/m2 + C 300 mg/m2). The median survival duration was best correlated with the P dose (4.8 months for doses < 175 mg/m2 v 7.9 months for doses > or = 175 mg/m2, P = .07; P-T > or = 0.1 mumol/L, 4.8 months for < 15 hours v 8.2 months for > or = 15 hours, P = .06).
  
  
  CONCLUSIONS
  There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter P-T > or = 0.1 mumol/L was related to improved survival in this study.
authors.affiliation: Department of Medical Oncology and Pulmonology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: M T
authors.initials: MT
authors.lastname: Huizing
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
authors.forename: L J
authors.initials: LJ
authors.lastname: van Warmerdam
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.forename: P J
authors.initials: PJ
authors.lastname: Bakker
authors.forename: J B
authors.initials: JB
authors.lastname: Vermorken
authors.forename: P E
authors.initials: PE
authors.lastname: Postmus
authors.forename: N
authors.initials: N
authors.lastname: van Zandwijk
authors.forename: M G
authors.initials: MG
authors.lastname: Koolen
authors.forename: W W
authors.initials: WW
authors.lastname: ten Bokkel Huinink
authors.forename: W J
authors.initials: WJ
authors.lastname: van der Vijgh
authors.forename: F J
authors.initials: FJ
authors.lastname: Bierhorst
authors.forename: A
authors.initials: A
authors.lastname: Lai
authors.forename: O
authors.initials: O
authors.lastname: Dalesio
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
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; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016019:Survival Analysis
chemical_list: D016190:Carboplatin; D017239:Paclitaxel