No evidence that amifostine influences the plasma pharmacokinetics of topotecan in ovarian cancer patients.
ABSTRACT This aim of this study was to compare the pharmacokinetics of topotecan in the presence and absence of preceding amifostine to reduce the risk of side effects in patients with advanced ovarian cancer.
Ten patients with advanced ovarian cancer received topotecan, 1.5 mg/m(2) for 5 days, as second-line therapy in an open phase-II study after previous platinum-containing first-line therapy. Patients were randomised to receive intravenous (IV) amifostine at a daily dose of 300 mg/m(2) prior to topotecan in the first cycle and topotecan alone in the second cycle or vice versa. Thereafter all patients were given amifostine and topotecan for additional four cycles. Topotecan was given as a 30-min IV infusion. On day 1 of the first and second treatment cycles, venous blood samples were collected up to 24 h after the start of topotecan infusion. Plasma concentrations of total topotecan and its active lactone form were determined using high-performance liquid chromatography.
There was a rapid decline in total topotecan plasma concentrations after the end of the infusion followed by a slower decay. The initial decline was even faster for the lactone form. The inter-individual variability was pronounced and the area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)) of the total topotecan plasma concentration ranged from 182 nmol/l h to 725 nmol/l h for topotecan alone and from 188 nmol/l h to 574 nmol/l h for topotecan and amifostine. The geometric mean of AUC(0-infinity) values were 326 nmol/l h and 297 nmol/l h, respectively ( P=0.41). In the cycles when the patients received topotecan alone, the plasma AUC of the lactone averaged 40% of the AUC of the total concentration compared with 39% in the cycles when topotecan was given after amifostine. The peak plasma concentration (C(max)) of the lactone averaged 72% of the C(max) of the total topotecan concentration in the topotecan-only group. The corresponding figure after topotecan and amifostine was 80% ( P=0.11). A large intra-individual pharmacokinetic of topotecan between cycles 1 and 2 was also observed.
Amifostine, 300 mg/m(2), does not significantly affect the pharmacokinetics of topotecan and there are pronounced intra- and inter-individual variabilities in the topotecan pharmacokinetics.
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ABSTRACT: Amifostine (Ethyol) administered to cancer patients is rapidly cleared from plasma by a biphasic decay with an alpha half-life (T1/2 alpha) of 0.88 min and a T1/2 beta of 8.8 min. The result is that more than 90% of the drug has disappeared from the plasma compartment 6 min after intravenous (i.v.) administration. Only approximately 1% of the dose appears in the ascites. Animal studies indicate that amifostine is primarily excreted in urine-approximately 6% of the dose is excreted in the urine as amifostine and its metabolites WR-1065 and disulphides-which means that a large percentage of the dose is taken up by the tissues. Maximal tissue concentrations of WR-1065 and the disulphides were obtained between 10 and 30 min after an intraperitoneal injection of amifostine in mice, with the lowest concentrations in tumour tissues. Because WR-1065 gives protection to normal tissues rather than rescue, the pharmacokinetic data indicate that amifostine must be given shortly before administration of the cytostatic drug or radiation from which protection is required. For these reasons, amifostine is given to patients as a 15-min i.v. infusion before cisplatin and carboplatin to protect against their dose-limiting toxicities. In some regimens carboplatin is combined with three doses of amifostine because of the high concentration of the active carboplatin species during the first 4 h after administration. When carboplatin was administered as a 15-min i.v. infusion of 400 mg/m2 and amifostine as a 15-min i.v. infusion of 740 mg/m2 just before and 2 and 4 h after carboplatin, the area under the plasma concentration-time curve for ultrafilterable platinum increased from 253 +/- 45 microM.h (n = 6) for carboplatin alone to 305 +/- 63 microM.h (n = 11) for carboplatin+three doses of amifostine. Experiments in nude mice bearing OVCAR-3 xenografts showed that amifostine, given once before cisplatin or three times in combination with carboplatin, did not affect the antitumour effect of these drugs. When amifostine was only given just before carboplatin, it even stimulated the antitumour effect of carboplatin significantly.European Journal of Cancer 02/1996; 32A Suppl 4:S26-30. · 5.06 Impact Factor
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ABSTRACT: The inter- and intraindividual variabilities in topotecan clearance (CL) were explored using a population pharmacokinetic approach. Total (lactone + hydroxy acid) topotecan plasma concentrations were obtained in 31 women with metastatic epithelial ovarian cancer treated by the 30-min intravenous infusion on 5 subsequent days. The data corresponding to three occasions (days 1 and 5 of cycle 1, and day 1 of cycle 2), were analyzed using the nonlinear mixed effect model program. A large interindividual variability was observed, with CL varying from 9.1 to 42.51 per hour (mean 21.0). Topotecan CL was related to serum creatinine level, and age. A close relationship was also observed between topotecan CL and creatinine clearance. Intraindividual variability both within cycle 1 and between the two first cycles was limited, with a mean variation of -2+/-17%, and + 5+/-20%, respectively. A limited sampling strategy using Bayesian estimation based on two samples (5 min before the end of the 30-min infusion, and 4 h after the end of infusion) was developed. The results of this study combine relationships between topotecan pharmacokinetic parameters and patient covariates that may be useful for a priori dose adjustment, and convenient sampling procedure that can be used for further studies and drug monitoring.Cancer Chemotherapy and Pharmacology 02/2000; 46(5):375-81. · 2.80 Impact Factor
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ABSTRACT: The pharmacokinetics of amifostine, a protector against chemotherapy and radiation-induced toxicities, was investigated in the plasma and ascites of a cancer patient. A high-performance liquid chromatography (HPLC) procedure with electrochemical detection was used to measure amifostine, its active metabolite, WR 1065, and the disulfides (symmetrical plus mixed disulfides). Both amifostine and WR 1065 were rapidly cleared from the plasma (95% and 50% of the peak concentration within 1 h, respectively). The disulfides, which were rapidly formed from WR 1065, were cleared much more slowly (final half-life 13.6 h). Multiple dosing resulted in a tendency toward increasing peak levels of WR 1065 and decreasing peak levels of the disulfides. Only 1% of the delivered dose appeared in the ascites. Therefore, it is not plausible that the presence of ascites or other third spaces would have an impact on the pharmacokinetics of amifostine.Cancer Chemotherapy and Pharmacology 02/1996; 39(1-2):162-6. · 2.80 Impact Factor