No evidence that amifostine influences the plasma pharmacokinetics of topotecan in ovarian cancer patients

Abstract

Objective. 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.

Methods. Ten patients with advanced ovarian cancer received topotecan, 1.5 mg/m² 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/m² 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.

Results. 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–∞) 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–∞ 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.

Conclusion. Amifostine, 300 mg/m², does not significantly affect the pharmacokinetics of topotecan and there are pronounced intra- and inter-individual variabilities in the topotecan pharmacokinetics.