Population pharmacokinetic and pharmacodynamic model of CP-101,606 following a 72-hour infusion in acute ischemic stroke patients

Abstract

CP-101,606 (CP) is an N-methyl-D-aspartate NR2B subunit selective receptor antagonist. Pathologic overactivation of NMDA receptors is implicated in the neurodegeneration following stroke. A 72-hr infusion of CP or placebo was started within 8 hours of onset of symptoms. NONMEM was used for pharmacokinetic-pharmacodynamic modeling. A linear one-compartment mixture model describing fast and slow metabolizers with allometrically scaled clearance and volume described pharmacokinetics. Disease progression for stroke recovery (National Institute of Health Stroke Scale (NIHSS)) was modeled with an Emax function for recovering subjects and a linear function for subjects that worsened. The results suggested higher initial NIHSS, larger lesion volumes and older age negatively impacted rate and extent of recovery. Exposure to CP resulted in faster rate of recovery and larger maximum recovery in a concentration dependent manner. The statistical significance of including the effect of CP on the rate of recovery was somewhat low but reduced inter-patient variability in the disease progression model. Clinical Pharmacology & Therapeutics (2004) 75, P97–P97; doi: 10.1016/j.clpt.2003.11.370