Dose range finding study to determine the cardiovascular toxicokinetics of a single subcutaneous dose of B201 (NSC-710295D) in Cynomolgus monkeys.

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B201 is a dimeric bradykinin antagonist which inhibits cell proliferation and stimulates apoptosis in small-cell lung cancers and many non-small-cell lung cancers. A single subcutaneous injection of B201 at doses of 3, 5, or 7 mg/kg were administered to six Cynomolgus monkeys to determine the cardiovascular toxicokinetics and the no cardiovascular effect dose. B201 plasma concentrations peaked within 5 to 10 minutes for 5 of the 6 animals, with B201 not detected after 1 hour in 1 animal, after 4 hours in 4 animals and after 8 hours in one animal. Noncompartmental analysis was used to estimate PK parameters for 5 of the 6 animals. Good linear correlation was not achieved between dose and AUC possibly due to the small number of animals and/or the narrow dose range. Terminal t1/2 ranged from 1 to 3 hours. Because of unknown systemic bioavailability, meaningful clearance values and volumes of distribution could not be computed. No blood pressure or heart rate alterations were observed in either the 3 or 5 mg/kg dose groups. However, increases in blood pressure and heart rate were associated with B201 administered at 7 mg/kg, occurring between 8 and 18 hours post dosing. During this period, mean arterial pressure increases ranged from 23 to 30 percent when compared to baseline, while heart rate increases ranged from 20 to 45 percent when compared to baseline mean heart rate. Mean arterial pressures returned to near baseline by 20 hours post dosing, whereas heart rate increases were modestly and sporadically higher for up to 4 days post dosing. The blood pressure increase at the 7 mg/kg dose level appeared greater in the male animal when compared to the female animal. Body temperature was unaffected at any of the dose levels administered. There were no alterations in ECG intervals, rhythm or morphology that could be attributed to administration of B201. There were no apparent cardiovascular affects of B201 at dose levels of 5 mg/kg or lower. Based on the results of this study, the 5 mg/kg dose level appears to be a no cardiovascular effect dose level. (Supported by NCI Contract NO1-CM-87028).