A limited sampling method for estimation of the etoposide area under the curve

Abstract

A limited sampling method for estimation of the etoposide area under the curve (AUC) is presented. The method was developed and validated in 23 patients (42 pharmacokinetic studies) with small-cell lung cancer (SCLC), limited disease. The patients received 100 mg/m² etoposide as a 90-min intravenous infusion in combination with carboplatin, allowing for etoposide dose modification at a following course (25% increase or decrease) due to high or low nadir values for leukocytes or thrombocytes. Of the 42 pharmacokinetic studies, 27 were used in the model development and 15 were used in the model validation. Single regression analyses of the AUC versus the fitted concentrations for the model data set were performed at several time points. The analyses demonstrated high and essentially identical correlation coefficients in the interval between 2 and 21 h, with a maximal value of 0.96 being recorded at 4 h. Multiple regression analysis was then performed using fitted concentrations corresponding to 0.08–21 h. The best model for one sample was AUC =1.01x(dose level divided by 100 mg/m²)+799×C_{4 h}, that for two samples was AUC=1.43x(dose level divided by 100 mg/m²)+544×C_{4 h}+1756×C_{21 h}, and that for three samples was AUC=0.07x(dose level divided by 100 mg/m²)+110×C_{5 min}+474×C_{4 h}+1759×C_{21 h}. Not unexpectedly, the model validation revealed that the one-sample model was less precise than the two- or three-sample model [percentage of root mean squared error (RMSE%)=11.6%, 7.1%, and 5.4%, respectively]. All models proved to be unbiased in the validation [percentage of mean predictive error (MPE%) ±SE=4.2%±11.0%, 7.9%±6.1%, and 6.3%±5.3%, respectively]. The models were subsequently validated in 14 pharmacokinetic studies of patients with metastatic germ-cell tumours who were receiving combination chemotherapy with cisplain and bleomycin plus 100 mg/m² etoposide as a 90-min infusion. The RMSE% was 13.4%, 10.8%, and 9.0% and the MPE%±SE was −1.0%±11.9%, 1.7%±10.5%, and 2.7%±7.9% for the one-, two-, and three-sample models, respectively. The limited sampling methods presented herein may prove to be a most valuable tool for therapeutic drug monitoring in regimens in which etoposide is given in combination with carboplatin or with cisplatin and bleomycin.