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.
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ABSTRACT: Background Etoposide is a chemotherapeutic agent, widely used for the treatment of various malignancies, including small cell lung cancer (SCLC), an aggressive disease with poor prognosis. Oral etoposide administration exhibits advantages for the quality of life of the patient as well as economic benefits. However, widespread use of oral etoposide is limited by incomplete and variable bioavailability. Variability in bioavailability was observed both within and between patients. This suggests that some patients may experience suboptimal tumor cytotoxicity, whereas other patients may be at risk for excess toxicity. Conclusions The article highlights dilemmas as well as solutions regarding oral treatment with etoposide by presenting and analyzing relevant literature data. Numerous studies have shown that bioavailability of etoposide is influenced by genetic, physiological and environmental factors. Several strategies were explored to improve bioavailability and to reduce pharmacokinetic variability of oral etoposide, including desired and undesired drug interactions (e.g. with ketoconazole), development of suitable drug delivery systems, use of more water-soluble prodrug of etoposide, and influence on gastric emptying. In addition to genotype-based dose administration, etoposide is suitable for pharmacokinetically guided dosing, which enables dose adjustments in individual patient. Further, it is established that oral and intravenous schedules of etoposide in SCLC patients do not result in significant differences in treatment outcome, while results of toxicity are inconclusive. To conclude, the main message of the article is that better prediction of the pharmacokinetics of oral etoposide may encourage its wider use in routine clinical practice.Radiology and Oncology 03/2013; 47(1):1-13. DOI:10.2478/raon-2013-0008 · 1.67 Impact Factor
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ABSTRACT: The non-invasive detection of insulinomas remains a diagnostic problem that is not solved by means of somatostatin receptor scintigraphy. We investigated the biokinetics and specificity of uptake and degradation of the incretin hormone glucagon-like peptide-1 (GLP-1) in a rat insulinoma cell line (RINm5F) in order to ascertain whether radiolabelled GLP-1 may be suitable for specific visualisation of insulinomas in vivo. GLP-1 (7-36)amide was radioiodinated according to the iodogen method. The specificity of the uptake of [(125)I]GLP-1(7-36)amide by RINm5F cells was investigated. Degradation products of GLP-1 (7-36)amide in the cell medium were purified by HPLC. Their masses and amino acid sequences were determined by (252)Cf-plasma desorption mass spectrometry. Lysosomal degradation was inhibited and after differential centrifugation the amount of radiotracer incorporated into lysosomes was determined. Biodistribution studies were performed in a rat insulinoma model (NEDH rats and RINm5F cells) with [(123)I]GLP-1(7-36)amide and its more stable agonist [(123)I]exendin 3. The uptake of radiotracer into insulinoma cells reached a maximum within 5 min. It was inhibited by an excess of unlabelled peptide. [(125)I]GLP-1(7-36)amide accumulated in the cells if lysosomal degradation was inhibited. Degradation products of the peptide were found in the cell medium. We determined their mass and derived their amino acid sequence. Radiolabelling of exendin 3 was more difficult than that of GLP-1 because of the lack of tyrosine in its primary structure. Biodistribution studies showed rapid blood clearance and uptake of the radiotracer into the tumour and the pancreas. It was also possible to detect insulinomas in an animal model by external scintigraphy using radioiodinated GLP-1 (7-36)amide and exendin 3. GLP-1 (7-36)amide is specifically internalised into insulinoma cells by a receptor-mediated mechanism. Our results demonstrate that GLP-1 receptor-directed scintigraphy may be a new method for the detection of insulinomas in vivo. Due to the short half-life of GLP-1, its more stable analogue exendin 3 may better suit this purpose in vivo.European journal of nuclear medicine and molecular imaging 06/2002; 29(5):597-606. DOI:10.1007/s00259-002-0761-1 · 5.22 Impact Factor
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ABSTRACT: Purpose: To conduct a systematic review of available limited sampling strategies (LSSs) for all anticancer (other than platinum) agents and to assess the clinical utility of such models. Design: A literature search was conducted using PubMed and EMBASE up to November 2008. Relevant articles were then categorized according to modified level of evidence guidelines of the U.S. Preventive Services Task Force. Results: Fifty-one studies have been published suggesting LSSs for the estimation of pharmacokinetic (PK) parameters for 16 different anticancer agents. These include [number of studies (n) =1, unless otherwise denoted]: busulfan [levels II-1, II-2(n=6), III], cladribine (level II-1), cyclophosphamide (level II-1), docetaxel (level II-1, III), doxorubicin (level II-1), epirubicin [levels II-1, III(n=2)], etoposide [levels I(n=3), II-1(n=2), II-2, III], 5-fluorouracil [levels II-1, II-2, III(n=2)], irinotecan [levels I(n=2), II-2(n=3), III], melphalan (level I), methotrexate [level II-1(n=3), II-2], temozolamide (level I), thiotepa (level III), topotecan [levels I(n=3), II-1, II-2, III], vinblastine (level II-1) and vinorelbine [levels I, II-2(n=2)]. Conclusion: The 12 level I studies illustrate that when properly constructed and validated, LSSs have the ability to estimate PK parameters in cancer patients. However, the estimated PK parameters need to be related to clinical response or toxicity in order to demonstrate full clinical utility.Current Cancer Therapy Reviews 01/2009; 5(1):45-66. DOI:10.2174/157339409787314081