title: Intra-arterial administration of carboplatin and the blood brain barrier permeabilizing agent, RMP-7: a toxicologic evaluation in swine.
abstract: RMP-7 is a bradykinin B2 receptor agonist shown to permeabilize the blood-brain barrier, especially that associated with brain tumors, when administered via both intracarotid and intravenous routes. Both routes of administration are currently being tested in human trials in combination with the chemotherapeutic agent carboplatin as therapy for gliomas. As an essential prerequisite to the initial intracarotid clinical trials, the potential neurotoxicity of intra-arterial administration of RMP-7 (at a high or low dose), alone and in combination with carboplatin, was assessed in anesthetized Red Duroc swine. Five treatment groups were evaluated with each pig receiving a series of alternating, intra-arterial infusions of RMP-7 (or saline) followed by carboplatin (or saline), as follows: (1) vehicle control: saline/saline; (2) carboplatin only control: saline/carboplatin (50 mg total); (3) RMP-7 only control: RMP-7 (750 ng/kg)/saline; (4) low dose combination: RMP-7 (75 ng/kg)/carboplatin (50 mg total); and (5) high dose combination: RMP-7 (750 ng/kg)/carboplatin (50 mg total). For each subject, one of the alternating dosing sequences (above) was repeated four times during a single dosing session which lasted approximately 40 minutes. Assessments during the in-life phase of the study in the pre- and post-treatment periods consisted of heart rate, arterial blood pressure (systolic, diastolic, and mean), blood gases, body weight, general clinical observations (including evaluation for neurological deficit) and clinical pathology (including a comprehensive battery of standard blood coagulation, hematological and serum chemistry tests). In addition, during the time of treatment, heart rate and arterial blood pressure were monitored. The animals were terminated two weeks after dosing and the brain and rete mirabile (distal to site of infusion) were evaluated for gross and histopathological abnormalities. The histopathology analysis included a reader-blinded analysis using low and high power light microscopic examination of both H&E and Kluver-Berrera stained sections through several key cortical and subcortical brain regions. Transient decreases in arterial blood pressure (mean of 10-25 mmHg) were observed in both groups receiving the high dose of RMP-7 (i.e., 750 ng/kg). No other side effects attributable to RMP-7 and/or carboplatin were observed, and clinical observations revealed no evidence of neurologic deficits. Post-mortem examination revealed no evidence of CNS or cerebral vascular pathology attributable to carboplatin and RMP-7. This study demonstrates that intracarotid administration of the maximum tolerated dose of RMP-7 (750 ng/kg) alone, or in combination with carboplatin (50 mg) is not accompanied by any serious adverse effect, apparent cerebrovascular abnormality or neuropathologic consequence and offers further evidence for the safety of this novel therapeutic approach for enhancing delivery of chemotherapeutics to brain tumors.
authors.affiliation: Alkermes, Inc., Cambridge, MA 02139, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Riley
authors.forename: N N
authors.initials: NN
authors.lastname: Kim
authors.forename: V E
authors.initials: VE
authors.lastname: Watson
authors.forename: Y P
authors.initials: YP
authors.lastname: Gobin
authors.forename: C P
authors.initials: CP
authors.lastname: LeBel
authors.forename: K L
authors.initials: KL
authors.lastname: Black
authors.forename: R T
authors.initials: RT
authors.lastname: Bartus
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000633:toxicity; D002199:Capillary Permeability / Q000187:drug effects; D016190:Carboplatin / Q000633:toxicity*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004334:Drug Administration Schedule; D007022:Hypotension / Q000139:chemically induced; D007261:Infusions, Intra-Arterial; D008297:Male; D008954:Models, Biological; D013552:Swine
chemical_list: D000970:Antineoplastic Agents; C089876:RMP 7; D016190:Carboplatin; D001920:Bradykinin