[2000]-[BNP7787]-[Pharmacokinetics of BNP7787 (dimesna) and its metabolite mesna in plasma and ascites.]
[Proceedings of the 11th NCI · EORTC · AACR Symposium]
Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy
Published by the AACR.
346 Pharmacokinetics of BNP7787 (dimesna) and its metabolite mesna in plasma and ascites.
Does a pharmacokinetic interaction occur between BNP7787 and (hydrated) cisplatin in cancer patients?
M. Verschraagen1 E. Boven1, M. Westerman1, R. Ruijter1, F.H. Hausheer2, D. Reddy2 and W.J.F. van der Vijgh1. 1University Hospital Vrije Universiteit, Amsterdam, The Netherlands; 2BioNumerik Pharmaceuticals, Inc., San Antonio, USA.
The disulphide BNP7787 (dimesna) is believed to be a non-toxic novel protector against cisplatin-induced toxicities. In the kidneys, BNP7787 is intracellularly converted into mesna, which can locally inactivate toxic platinum species.
In a phase I trial, patients with solid tumors received a fixed dose of 75 mg/m2 cisplatin in a 1-hour infusion. Three weeks later they received cisplatin immediately preceded by a 15-min infusion of BNP7787. BNP7787 was also given alone one week prior to the cycle with cisplatin. The dose of BNP7787 was escalated from 4.1 g/m2 to 41 g/m2. Cmax and AUC increased linearly with the dose. Vss and total body Cl (±S.D.) were 0.261±0.081 l/kg and 9.2±2.9 l/h/1.73 m2, respectively. At the highest dose levels, BNP7787 did not influence the pharmacokinetics (PK) of (hydrated) cisplatin, unbound platinum and total platinum. The mean AUC/dose values (±S.D.) of BNP7787 with and without cisplatin were 200±48 and 217±38.10-3h.m2/l and of mesna 16.3±7.3 and 15.6±6.8.10-3h.m2/l, respectively. Without and with cisplatin the mean final half-lives (±S.D.) of BNP7787 were 1.4±0.4 and 1.4±0.6 h and of mesna 2.7±1.8 and 2.8±3.2 h, respectively. In conclusion, cisplatin did not influence the PK of BNP7787 and mesna. In one patient with ascites, BNP7787 41 g/m2 was given alone and after one week in combination with cisplatin. Recovered volumes of ascites were 4.8 and 1.7 l, respectively. PK values of BNP7787 and mesna (i.e. AUC, t1/2, Cl and Vss) in plasma in the patient with ascites did not significantly differ from the values obtained from patients without ascites. In ascites approximately 0.02% of the BNP7787 dose was present as mesna, whereas 4% of the dose was present as BNP7787 at the time of the maximum concentration. In conclusion, the presence of ascites did not have a major impact on the PK of BNP7787.
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