Pharmacokinetics of paclitaxel and carboplat dose-escalating and dose-sequencing study in with non-small-cell long cancer

Purpose: 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. Patients and 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/m(2), and C over 30 minutes at dosages of 300 to 400 mg/m(2). 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-C-max), or time above a threshold concentration of 0.1 mu mol/L (P-T greater than or equal to 0.1 mu mol/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/m(2) 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/m(2) + C 300 mg/m(2)). The median survival duration was best correlated with the P dose (4.8 months for doses < 175 mg/m(2) v 7.9 months for doses greater than or equal to 175 mg/m(2), P = .07; P-T greater than or equal to 0.1 mu mol/L, 4.8 months for < 15 hours v 8.2 months for greater than or equal to 15 hours, P = .06). Conclusion: 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 PT greater than or equal to 0.1 mu mol/L was related to improved survival in this study. (C) 1997 by American Society of Clinical Oncology.