Pharmacokinetics and preliminary clinical data of the novel chemoprotectant BNP7787 and cisplatin and their metabolites.
BACKGROUND
BNP7787 (disodium 2,2'-dithio-bis-ethane sulfonate) is currently undergoing development as a chemoprotective agent to prevent common and serious cisplatin-induced side effects. In the kidneys, intestine, and liver, BNP7787 is believed to undergo intracellular conversion into 2-mercaptoethane sulfonate (mesna), which can locally inactivate toxic platinum species. Methods and objectives In a phase I trial, 25 patients with advanced solid tumors received a 1-hour intravenous infusion of 75 mg/m(2) cisplatin immediately preceded by a 15-minute intravenous infusion of BNP7787 every 3 weeks. For pharmacokinetic investigation of BNP7787 and mesna and a possible mutual pharmacokinetic interaction between BNP7787 and cisplatin, cisplatin and BNP7787 were also administered as single agents in 14 of 25 patients. The dose of BNP7787 was escalated from 4.1 to 41 g/m(2). Patients were also monitored for tumor response and possible side effects from BNP7787.


RESULTS
The maximum plasma concentration of mesna was reached approximately 1.7 hours after the start of the BNP7787 infusion. The maximum plasma concentration and area under the curve to infinity (AUC( infinity )) of BNP7787 and mesna increased linearly with the dose. The mean volume of distribution of BNP7787 (+/-SD) was approximately 0.26 +/- 0.08 L/kg. The mean normalized AUC( infinity ) of mesna was only approximately 8% of the normalized AUC( infinity ) of BNP7787. The pharmacokinetic profile of mesna was unaffected by cisplatin and its metabolites. None of the dose levels of BNP7787 (4.1-41 g/m(2)) administered appeared to influence the pharmacokinetic profile of total platinum, unbound platinum, or monohydrated cisplatin. The observed effects regarding a possible mutual interaction between BNP7787 and intact cisplatin were minor, and none were statistically significant at BNP7787 dose levels of 18.4 to 41 g/m(2). The confidence intervals for the pharmacokinetic parameters of BNP7787 and intact cisplatin, however, were relatively broad. Overall, BNP7787 was well tolerated at all dose levels (4.1-41.0 g/m(2)). The most frequently reported event related to BNP7787 was local intravenous site discomfort; the majority of events were mild (grade 1). Side effects of BNP7787 at the highest dose level of 41 g/m(2) were more prominent and included nausea and vomiting, as well as a warm feeling or flushing (grade 2 or lower). Partial tumor responses and stable disease were measured in 12 of 25 patients.


CONCLUSIONS
BNP7787 was relatively nontoxic at doses up to 41 g/m(2). The combination of BNP7787 with cisplatin did not alter the pharmacokinetic profiles of mesna or the cisplatin metabolites. At the higher dose levels of BNP7787 (18.4 to 41 g/m(2)), there appeared to be no mutual interaction between BNP7787 and intact cisplatin, which needs to be confirmed in a larger number of patients. The absence of a mutual interaction between BNP7787 and intact cisplatin is consistent with the observation that several patients had objective tumor responses with BNP7787 and cisplatin administration.
Verschraagen
Miranda
M
Department of Medical Oncology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. M.Verschraagen@vumc.nl
Boven
Epie
E
Ruijter
Rita
R
van der Born
Kasper
K
Berkhof
Johannes
J
Hausheer
Frederick H
FH
van der Vijgh
Wim J F
WJ
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000493:pharmacokinetics*; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D015080:Mesna / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008875:Middle Aged; D010984:Platinum / Q000097:blood; D011446:Prospective Studies; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D004338:Drug Combinations; D010984:Platinum; C027032:2,2'-dithiodiethanesulfonic acid; D015080:Mesna; D002945:Cisplatin