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Titolo:
ETOPOSIDE BIOAVAILABILITY AFTER ORAL-ADMINISTRATION OF THE PRODRUG ETOPOSIDE PHOSPHATE IN CANCER-PATIENTS DURING A PHASE-I STUDY
Autore:
CHABOT GG; ARMAND JP; TERRET C; DEFORNI M; ABIGERGES D; WINOGRAD B; IGWEMEZIE L; SCHACTER L; KAUL S; ROPERS J; BONNAY M;
Indirizzi:
INST GUSTAVE ROUSSY,PHARMACOL LAB,DEPT MED,RES PAVIL,39 RUE CAMILLE DESMOULINS F-94805 VILLEJUIF FRANCE INST GUSTAVE ROUSSY,DEPT BIOSTAT & EPIDEMIOL F-94805 VILLEJUIF FRANCE INST GUSTAVE ROUSSY,CLIN CHEM LAB F-94805 VILLEJUIF FRANCE BRISTOL MYERS SQUIBB CO WALLINGFORD CT 06492 BRISTOL MYERS SQUIBB CO PRINCETON NJ 00000
Titolo Testata:
Journal of clinical oncology
fascicolo: 7, volume: 14, anno: 1996,
pagine: 2020 - 2030
SICI:
0732-183X(1996)14:7<2020:EBAOOT>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
HIGH-DOSE ETOPOSIDE; CELL LUNG-CANCER; VP 16-213; ANTINEOPLASTIC EPIPODOPHYLLOTOXIN; RANDOMIZED TRIAL; PHARMACOKINETICS; VP-16-213; TUMORS; VP16-213; CHILDREN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
41
Recensione:
Indirizzi per estratti:
Citazione:
G.G. Chabot et al., "ETOPOSIDE BIOAVAILABILITY AFTER ORAL-ADMINISTRATION OF THE PRODRUG ETOPOSIDE PHOSPHATE IN CANCER-PATIENTS DURING A PHASE-I STUDY", Journal of clinical oncology, 14(7), 1996, pp. 2020-2030

Abstract

Purpose: The purpose of this study was to determine the bioavailability (F) of etoposide (E; VP-16) after oral administration of the water-soluble prodrug etoposide phosphate (EB; BMY-40481) during a phase I trial in cancer patients. Patients and Methods: Twenty-nine patients received oral EP (capsules 50 to 150 mg/m(2)/d of E equivalent) for 5 days in week 1 (course 1), followed every 3 weeks thereafter by a daily intravenous (IV) infusion for 5 days of E (80 mg/m(2), 1-hour IV infusion; course 2); in three patients, the IV E course was given before oral EP. Plasma and urine E pharmacokinetics (high-performance liquid chromatography [HPLC]) were performed on the first day of oral EP administration and on the first day of IV E. Results: Twenty-six of 29 patients completed two courses or more, whereas three patients received only one course due to toxicity, Myelosuppression was dose-dependent and dose-limiting, with grade 4 leukoneutropenia in four of 15 patients at125 mg/m(2) and in five of seven patients at 150 mg/m(2), One patientdied of meningeal hemorrhage related to grade 4 thrombocytopenia. Other toxicities wore infrequent and/or manageable. No objective responsewas observed. The maximum-tolerated dose (MTD) is therefore 150 mg/m(2), and the recommended oral dose of EP for phase II trials in this poor-risk patient population is 125 mg/m(2). Twenty-six patients had pharmacokinetic data for both oral EP and IV E, whereas three had pharmacokinetic data on the IV E course only. After oral administration of EP, the pharmacokinetics of E were as follows: mean absorption rate constant (Ka), 1.7 +/- 1.7 h(-1) (mean I SD); lag time, 0.3 +/- 0.2 hours;time of maximum concentration (t(max)), 1.6 +/- 0.8 hours; and mean half-lives (t(1/2)), 1.6 +/- 0.2 (first) and 10.3 +/- 5.8 hours (terminal); the increase in the area under the plasma concentration-versus-time curve (AUG) of E was proportional to the EP dose. After the 1-hour IV infusion of E, maximum concentration (C-max) was 15 +/- 3 mu g/mL; mean AUC, 88.0 +/- 22.0 mu g . h/mL; mean total-body clearance (CL), 0.97 +/- 0.24 L/h/m(2) (16.2 mL/min/m(2)); and mean t(1/2), 0.9 +/- 0.6(first) and 8.1 +/- 4.1 hours (terminal), The 24-hour urinary excretion of E after IV E was significantly higher (33%) compared with that of oral EP (17%) (P < .001). Significant correlation was observed between the neutropenia at nadir and the AUC of E after oral EP administration (r = .58, P < .01, sigmoid maximum effect [E(max)] model), The mean F of E after oral administration of EP in 26 patients was 68.0 +/- 17.9% (coefficient of variation [CV], 26.3%; F range, 35.5% to 111.8%). In this study, tumor type, as well as EP dose, did nor significantly influence the F in E. There was no difference in F of E, whether oral EP was administered before or after IV E. Compared with literature data an oral E, the percent F in E after oral prodrug EP administration was 19% higher at either low (less than or equal to 100 mg/m(2)) or high (> 100 mg/m(2)) doses. Conclusion: Similarly to E, the main toxicityof the prodrug EP is dose-dependent leukoneutropenia, which is dose-limiting at the oral MTD of 150 mg/m(2)/d for 5 days. The recommended oral dose of EP is 125 mg/m(2)/d for 5 days every 3 weeks in poor-risk patients. Compared with literature data, oral EP has a 19% higher F value compared with oral E either at low or high doses. This higher F inE from oral prodrug EP appears to be a pharmacologic advantage that could be of potential pharmacodynamic importance for this drug. (C) 1996 by American Society of Clinical Oncology.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/12/20 alle ore 00:03:08