An Open‐Label Study of CP‐101,606 in Subjects with a Severe Traumatic Head Injury or Spontaneous Intracerebral Hemorrhage

Abstract

CP-101,606 is a postsynaptic antagonist of N-methyl-D-aspartate (NMDA) receptors bearing the NR2B subunit. When administered intravenously (i.v.), it decreases the effects of traumatic brain injury (TBI) and focal ischemia in animal models. Therapeutic plasma concentrations (200 ng/ml) in animals, have been well tolerated in healthy human volunteers. The purpose of the present dose escalation study was to assess the safety, tolerability, and pharmacokinetics of CP-101,606 in subjects who had suffered either an acute severe TBI (Glasgow Coma Scale 3-8) or spontaneous intracerebral hemorrhage. Thirty patients, 20 with a TBI and 10 with a stroke, were enrolled in the trial and began receiving an i.v. infusion of CP-101,606 for 2 hours, 24 hours, or 72 hours within 12 hours of brain injury. For the first two hours, the drug was given a rate of 0.75 mg/kg/hr and then stopped (n = 17) or continued for 22 (n = 2) or 70 hours (n = 11) at 0.37 mg/kg/hr. Plasma and cerebrospinal fluid (CSF) were collected at serial times during and after treatment. There were no consistent changes in blood pressure or pulse nor any clinically significant hematological or electrocardiogram (ECG) abnormalities attributable to CP-101,606. No adverse events or behavioral changes were considered to be related to the drug. Plasma concentrations of CP-101,606 over 200 ng/ml were rapidly achieved in the blood and CSF within two hours and were sustained there as long as the drug was infused. CSF concentrations were slightly higher than that in plasma by the end of infusion suggesting good penetration of CP-101,606 into the CSF. Outcome in the severe TBI patients, as measured by the Glasgow Outcome Score at six months, suggested that a two-hour infusion yielded a range of scores similar to contemporary patients with a severe TBI treated at our hospital while the outcomes of the patients treated with either a 24- or 72-hour infusion were better on average. Thus, these results indicate that CP-101,606 infused for up to 72 hours is well tolerated, penetrates the CSF and brain, and may improve outcome in the brain-injured patient.

The Disposition, Metabolism, and Pharmacokinetics of a Selective Metabotropic Glutamate Receptor Agonist in Rats and Dogs

“…Although the disposition of excitatory amino acid-like compounds has been previously reported (Duncan et al, 1991;Albers et al, 1999;Bullock et al, 1999), nearly all reports describe the disposition of ionotropic receptor agonists or antagonists. By comparison, relatively little information has been published on the physiological role (Lang and Ajmal, 1995), metabolism, or disposition of a metabotropic receptor agonist.…”

Pharmacological Characterization of Ro 63-1908 (1-[2-(4-Hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a Novel Subtype-SelectiveN-Methyl-d-Aspartate Antagonist

“…They have advantages over nonselective competitive and ion channel-blocking NMDA antagonists in that they have a much improved tolerability in animals and also, based on initial reports, in humans Bullock et al, 1999). Therefore, it is conceivable that maximally neuroprotective doses of these compounds could be achieved in humans without cardiovascular or CNS side effects.…”

Ion Channels as Drug Targets in Central Nervous System Disorders

“…In humans it was well tolerated, penetrated the brain, and showed improvement in brain injury [232]. In a double-blind, placebocontrolled study of the safety, tolerability and pharmacokinetics of traxoprodil in patients with a mild or moderate traumatic brain injury it had no psychotropic effects and was well-tolerated in patients [232]. Moreover, the compound had direct antiparkinsonian actions in rodents (decreased haloperidol-induced catalepsy with ED 50 =0.5 mg/kg) and monkeys (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MP TP)-treated monkeys, traxoprodil (1 mg/kg)) [233].…”

“…Moreover, this drug exhibits a 69% reduction in infarct size in comparison to controls [232]. In humans it was well tolerated, penetrated the brain, and showed improvement in brain injury [232]. In a double-blind, placebocontrolled study of the safety, tolerability and pharmacokinetics of traxoprodil in patients with a mild or moderate traumatic brain injury it had no psychotropic effects and was well-tolerated in patients [232].…”