Pharmacokinetics of carboplatin administered in combination with the bradykinin agonist Cereport (RMP-7) for the treatment of brain tumours

Introduction: Cereport (RMP-7) is a novel bradykinin agonist which is being developed as a modulator of the blood-brain barrier (BBB). In order to inv estigate the pharmacokinetics of carboplatin in combination with Cereport. we performed pharmacological studies in conjunction with early clinical tri als. Methods: Pharmacokinetic samples were collected from sight patients in a phase I study (Cereport 100-300 ng/kg) and ten patients in a phase II st udy (Cereport 300 ng/kg). Pharmacokinetic parameters for carboplatin were c ompared with respect to the dose of Cereport and with historical controls. Results: Cereport combined with carboplatin was well-tolerated, with mild h aematological toxicities consistent with the target area under the concentr ation-time curve (AUC) of 7 mg/ml*min. Although the clearance of carboplati n was within the range reported for this drug alone, the addition of Cerepo rt resulted in a higher than expected carboplatin AUC. This effect was rela ted to the dose of Cereport in the phase I study (AUC values 10 104-133% of target, Spearman rank correlation coefficient = 0.71. P < 0.001). The high er than expected AUC value was confirmed in the phase II study (AUC values 106-189% of target). Conclusions: Co-administration of Cereport with carbop latin may result in a greater than predicted AUC. The mechanism of this pos sible interaction remains to be determined. although this did not result in any increased toxicity. Thus, the clinical potential of this combination i n the treatment of brain tumours warrants further investigation.