PURPOSE: Paclitaxel is a taxane derivative with a profound antitumor activity against a variety of solid tumors. In a previous clinical study in patients with non-small cell lung cancer (NSCLC) treated with paclitaxel, it was shown that paclitaxel plasma concentrations of 0.1 micro mol/liter for > or = 15 h were associated with prolonged survival. The purpose of this study was to evaluate the feasibility of Bayesian dose individualization to attain paclitaxel plasma concentrations >0.1 micromol/liter for > or = 15 h. EXPERIMENTAL DESIGN: Patients with stage IIIb-IV NSCLC were treated with paclitaxel and carboplatin once every 3 weeks for a maximum of six courses. During the first course, a standard paclitaxel dose of 175 mg/m(2) was administered i.v. in 3 h. In subsequent courses, the paclitaxel dose was individualized based on observed paclitaxel concentrations in plasma during the previous course(s) using a Bayesian algorithm. The paclitaxel dose of a subsequent course was increased to the lowest dose for which the predicted time period during which the paclitaxel plasma concentration exceeds 0.1 micromol/liter was >15 h. RESULTS: A total of 25 patients have been included in the study (92 evaluable courses). During the first course, the median time period above the threshold concentration was 16.3 h (range, 7.6-31.6 h), and was <15 h for 9 patients (36%). During subsequent individualized courses, the time period above the threshold concentration was <15 h in 23% (5 of 22), 14% (2 of 14), 23% (3 of 13), 11% (1 of 9), and 11% (1 of 9) of the patients in the second, third, fourth, fifth, and sixth course, respectively. Dose increments, ranging from 5 to 65 mg/m(2), were performed in 29 of the 67 individualized courses. Patients with increased individualized doses had similar regimen related toxicities compared with those remaining at a dose of 175 mg/m(2). Toxicity was reversible and manageable, and was mainly hematological (granulocytopenia CTC grade 3/4 in 80% of the patients). The objective response rate was 20%. CONCLUSIONS: The results indicate that the applied pharmacokinetically guided dosing strategy for paclitaxel is safe and technically feasible. A randomized study is necessary to demonstrate whether dose individualization may result in improved activity and efficacy in patients with NSCLC.
PURPOSE:Paclitaxel is a taxane derivative with a profound antitumor activity against a variety of solid tumors. In a previous clinical study in patients with non-small cell lung cancer (NSCLC) treated with paclitaxel, it was shown that paclitaxel plasma concentrations of 0.1 micro mol/liter for > or = 15 h were associated with prolonged survival. The purpose of this study was to evaluate the feasibility of Bayesian dose individualization to attain paclitaxel plasma concentrations >0.1 micromol/liter for > or = 15 h. EXPERIMENTAL DESIGN:Patients with stage IIIb-IV NSCLC were treated with paclitaxel and carboplatin once every 3 weeks for a maximum of six courses. During the first course, a standard paclitaxel dose of 175 mg/m(2) was administered i.v. in 3 h. In subsequent courses, the paclitaxel dose was individualized based on observed paclitaxel concentrations in plasma during the previous course(s) using a Bayesian algorithm. The paclitaxel dose of a subsequent course was increased to the lowest dose for which the predicted time period during which the paclitaxel plasma concentration exceeds 0.1 micromol/liter was >15 h. RESULTS: A total of 25 patients have been included in the study (92 evaluable courses). During the first course, the median time period above the threshold concentration was 16.3 h (range, 7.6-31.6 h), and was <15 h for 9 patients (36%). During subsequent individualized courses, the time period above the threshold concentration was <15 h in 23% (5 of 22), 14% (2 of 14), 23% (3 of 13), 11% (1 of 9), and 11% (1 of 9) of the patients in the second, third, fourth, fifth, and sixth course, respectively. Dose increments, ranging from 5 to 65 mg/m(2), were performed in 29 of the 67 individualized courses. Patients with increased individualized doses had similar regimen related toxicities compared with those remaining at a dose of 175 mg/m(2). Toxicity was reversible and manageable, and was mainly hematological (granulocytopenia CTC grade 3/4 in 80% of the patients). The objective response rate was 20%. CONCLUSIONS: The results indicate that the applied pharmacokinetically guided dosing strategy for paclitaxel is safe and technically feasible. A randomized study is necessary to demonstrate whether dose individualization may result in improved activity and efficacy in patients with NSCLC.
Authors: Markus Joerger; Stefanie Kraff; Alwin D R Huitema; Gary Feiss; Berta Moritz; Jan H M Schellens; Jos H Beijnen; Ulrich Jaehde Journal: Clin Pharmacokinet Date: 2012-09-01 Impact factor: 6.447
Authors: Daniel L Hertz; Alison A Motsinger-Reif; Amy Drobish; Stacey J Winham; Howard L McLeod; Lisa A Carey; E Claire Dees Journal: Breast Cancer Res Treat Date: 2012-04-18 Impact factor: 4.872
Authors: Xinghe Wang; Gang Zhao; Sang Van; Nan Jiang; Lei Yu; David Vera; Stephen B Howell Journal: Cancer Chemother Pharmacol Date: 2009-07-11 Impact factor: 3.333
Authors: Bo Gao; Yi Lu; Annemieke J M Nieuweboer; Hongmei Xu; Jonathan Beesley; Ingrid Boere; Anne-Joy M de Graan; Peter de Bruijn; Howard Gurney; Catherine J Kennedy; Yoke-Eng Chiew; Sharon E Johnatty; Philip Beale; Michelle Harrison; Craig Luccarini; Don Conroy; Ron H J Mathijssen; Paul R Harnett; Rosemary L Balleine; Georgia Chenevix-Trench; Stuart Macgregor; Anna de Fazio Journal: Sci Rep Date: 2018-01-24 Impact factor: 4.379