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

Abstract

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 mol/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 mol/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/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 mol/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.

Quantitative Effect of Gender, Age, Liver Function, and Body Size on the Population Pharmacokinetics of Paclitaxel in Patients with Solid Tumors

“…Three compartments were used to describe paclitaxel pharmacokinetic data, in accordance to what has previously been reported (2,24,31). Our model suggested that nonlinear distribution of paclitaxel to the peripheral compartment is saturated at higher plasma concentrations (0.83 Amol/L for females and 1.74 Amol/L for males) compared with nonlinear elimination (0.53 Amol/L).…”

“…Plasma concentrationtime data of paclitaxel were collected during safety and pharmacokinetic studies in patients with NSCLC (30,31), ovarian cancer (32), and various solid tumors (33), accounting for a total of 168 cancer patients and 280 treatment courses, and submitted to population pharmacokinetic analysis. Patients were recruited from two multicenter studies (30,32) that studied paclitaxel at a dose of either 135 mg/m 2 (n = 2) or 175 mg/m 2 (n = 3) infused over 24 hours in women with recurrent epithelial ovarian cancer (32) and paclitaxel at a dose of 100 to 250 mg/ m 2 infused over 3 hours with concurrent carboplatin (300-400 mg/m 2 ) in patients with advanced NSCLC (n = 55; ref.…”

“…paclitaxel at a dose of 175 mg/ m 2 over 3 hours (33). Finally, 25 patients with advanced NSCLC were entered from a dose individualization study on paclitaxel (initial dose 175 mg/m 2 over 3 hours) and concurrent carboplatin (31). All studies were approved by the Medical Ethics Committees of the participating centers, and informed consent was obtained from all patients.…”

Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter?

“…The data were obtained from several previously published studies in which patients received carboplatin both in high-dose as well as in conventionaldose regimens in combination with other chemotherapeutic agents [10][11][12][13][14]. All protocols were approved by the Committee of Medical Ethics of the Netherlands Cancer Institute and written informed consent was obtained from all patients.…”

“…Pretreatment serum creatinine levels were estimated by the kinetic Jaffé method (Hitachi systems, Roche Diagnostics, The Netherlands) in three studies [12][13][14] and in the first 32 patients of one study [11], while in the remaining patients [10,11] the compensated Jaffé method was used. To correct for the different methods used, the serum creatinine values obtained with the kinetic Jaffé method were retrospectively adjusted by subtracting 26 lM from the initial values as proposed and validated by the manufacturer (Roche Diagnostics, The Netherlands).…”