Bayesian Pharmacokinetically Guided Dosing of Paclitaxel in Patients with Non-Small Cell Lung Cancer

Milly E. De Jonge, H. J.G.Desirée Van Den Bongard, Alwin D.R. Huitema, Ron A.A. Mathôt, Hilde Rosing, Paul Baas, Nico Van Zandwijk, Jos H. Beijnen, Jan H.M. Schellens

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41 Citaten (Scopus)

Samenvatting

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 μmol/liter for ≥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 μmol/liter for ≥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/m2 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 μmol/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/m2, 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/m2. 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.

Originele taal-2Engels
Pagina's (van-tot)2237-2244
Aantal pagina's8
TijdschriftClinical Cancer Research
Volume10
Nummer van het tijdschrift7
DOI's
StatusGepubliceerd - 1 apr. 2004
Extern gepubliceerdJa

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