TY - JOUR
T1 - Bayesian pharmacokinetically guided dosing of paclitaxel in patients with non-small cell lung cancer
AU - de Jonge, Milly E.
AU - van den Bongard, H. J. G. Desirée
AU - Huitema, Alwin D. R.
AU - Mathôt, Ron A. A.
AU - Rosing, Hilde
AU - Baas, Paul
AU - van Zandwijk, Nico
AU - Beijnen, Jos H.
AU - Schellens, Jan H. M.
PY - 2004
Y1 - 2004
N2 - 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. 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%. 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
AB - 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. 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%. 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
U2 - https://doi.org/10.1158/1078-0432.CCR-03-0060
DO - https://doi.org/10.1158/1078-0432.CCR-03-0060
M3 - Article
C2 - 15073098
SN - 1078-0432
VL - 10
SP - 2237
EP - 2244
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -