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 p aclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escal ating study in untreated non-small-cell lung cancer (NSCLC) patients. Patients and Methods: Fifty-five chemotherapy-naive patients with NSCL C 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). P atients were randomized for the sequence of administration, first C fo llowed by P or vice versa. Each patient received the alternate sequenc e during the second and subsequent courses. Results: The most importan t hematologic toxicity encountered was neutropenia. Hematologic toxici ty was not dependent on the sequence in which P and C were administere d, but there was cumulative neutropenia. Nonhematologic toxicities con sisted mainly of vomiting, myalgia, and arthralgia. No sequence-depend ent pharmacokinetic interactions for the P area under the concentratio n-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 e qual 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 pa tients, there were five major responders (three complete responders an d 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 surviva l 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 = .0 6). Conclusion: There was no pharmacokinetic-sequence interaction betw een C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic param eter 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 Oncol ogy.