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.
CONCLUSION:
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.