Limited sampling models for reliable estimation of etoposide area under the curve.
ABSTRACT Limited sampling models are able to estimate the area under the concentration-time curve (AUC) from plasma concentrations measured at only a few time points. The purpose of this study was to establish a model estimating etoposide AUC independently of specific chemotherapy protocols, underlying malignancies, concomitant diseases and age. Pharmacokinetic parameters were measured in 30 patients treated with polychemotherapy including etoposide (80-150 mg/m2). Etoposide analysis was performed by thin layer chromatography and consecutive quantitative sample detection by 252Cf-plasma desorption mass spectrometry. Data from the first 15 patients formed the training set. Based on the training data, five different models were generated, with the multiple regression coefficient r ranging from 0.91 to 0.96. The following model was selected as "most accurate": AUC = 343 (min)C4h(micrograms/ml) + 650(min)C8h(micrograms/ml) + 1252 (min micrograms/mol), where C4h is the plasma concentration of etoposide at 4 h after the end of infusion and C8h at 8 h. This model was validated on the test set, comprising the data of the remaining 15 patients. The mean predictive error (MPE) was -0.2% and the root mean square predictive error (RMSE) was 4.7%. When used for a large number of patients, this practicable and simple model is an instrument for use in prospective studies, to measure a correlation between drug dosage and efficacy or toxicity of the drug.
- Journal of Pharmaceutical Sciences - J PHARM SCI. 01/1978; 67(8):1106-1108.
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ABSTRACT: A new principle for plasma level monitoring of the anthracyclines doxorubicin and epirubicin is presented. The area under the plasma concentration time curve (AUC) is linearly correlated with the maximum plasma concentration of the drugs at the end of 2 and 4 hours' constant rate infusions. From this relationship it is possible to obtain accurate estimates of the AUC values of the drugs in the individual patients from plasma samples, withdrawn during the last 15 minutes prior to the completion of the infusions. The limited sampling model for drug monitoring of doxorubicin and epirubicin described here is robust and simple to use. It does not require a strict time control for the withdrawing of samples. Measured maximum plasma concentrations of epirubicin during 2 hours' constant rate infusions of 70 mg m-2 to patients with lymphoma (median age: 46.5 years) were within the range 171-404 ng ml-1 (median value: 265 ng ml-1).Acta Oncologica 02/1990; 29(3):339-42. · 2.87 Impact Factor
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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 = 1.01 x (dose level divided by 100 mg/m2) + 799 x C4 h, that for two samples was AUC = 1.43 x (dose level divided by 100 mg/m2) + 544 x C4 h + 1756 x C21 h, and that for three samples was AUC = 0.07 x (dose level divided by 100 mg/m2) + 110 x C5 min + 474 x C4 h + 1759 x C21 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 cisplatin 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.Cancer Chemotherapy and Pharmacology 02/1993; 32(3):226-30. · 2.80 Impact Factor