Bayesian pharmacokinetically guided dosing of paclitaxel in patients with non-small cell lung cancer.
OBJECTIVE
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.


METHODS
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.
de Jonge
Milly E
ME
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Slotervaart Hospital, Amsterdam, The Netherlands. apmil@slz.nl
van den Bongard
H J G Desirée
HJ
Huitema
Alwin D R
AD
Mathôt
Ron A A
RA
Rosing
Hilde
H
Baas
Paul
P
van Zandwijk
Nico
N
Beijnen
Jos H
JH
Schellens
Jan H M
JH
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D001499:Bayes Theorem; D016190:Carboplatin / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin