Bridging the Pharmacokinetics and Pharmacodynamics of UK-279,276 Across Healthy Volunteers and Stroke Patients Using a Mechanistically Based Model for Target-Mediated Disposition

Abstract

UK-279,276 is a recombinant glycoprotein and is a selective antagonist of CD11b, which in preclinical models of acute stroke blocks the infiltration of activated neutrophils into the site of infarction. Binding of UK-279,276 to the CD11b receptors is hypothesized to facilitate its elimination. The event of an acute stroke leads to proliferation of neutrophils and an up-regulation of CD11b, which results in different pharmacokinetics/pharmacodynamics (PK/PD) in patients than in healthy volunteers. The aim of this current analysis was to develop a mechanistically based model to bridge the differences between healthy volunteers and patients. PK samples, neutrophil counts, and total number and number of free CD11b receptors per neutrophils from three healthy volunteer studies (n=98) and one patient study (n=169) were modeled using the mixed effects modeling software NONMEM version VI (beta). Three mechanistic submodels were developed based on underlying physiology and pharmacology: (1) neutrophil maturation and proliferation, (2) CD11b up-regulation, and (3) three clearance pathways for UK-279-276 including CD11b-mediated elimination. The model accurately described the time course of CD11b expression, CD11b binding, and the measured PK of UK-279,276 and accounted for the PK/PD differences between healthy volunteers and patients. A complex mechanistic model that closely resembled the "true" underlying system provided an effective bridge between healthy volunteers and patients by appropriately accounting for the underlying disease-dependent target mediated disposition.