2001
   Basel, Switzerland

A mechanism based population PK/PD model of UK-279,276 in healthy volunteers and patients

E. N. Jonsson, F. Macintyre, I. James, W. Wild and S. Marshall

Department of Pharmaceutical Bioscienses, Uppsala University

UK-279,276 is a recombinant glycoprotein, derived from canine hookworm, and is an antagonist of the adhesion molecule CD11b/CD18. It is under development for the treatment of reperfusion injury following stroke. Both PK and PD (duration of maximal CD11b saturation) increase supra-proportionately with dose.

A total of 255 individuals from three healthy volunteer studies and one patient safety study, received 15-minute infusions of placebo or doses between 0.06 and 1.50 mg/Kg. Data on neutrophil counts, total number of CD11b receptors per neutrophil, number of non-occupied CD11b receptors per neutrophil and unbound plasma concentrations, were available for analysis.

A model with mixed linear and non-linear elimination and a non-specific, saturable, binding component was developed for the PK of UK-276,279. The model for the CD11b receptor binding, which incorporated the neutrophil counts as well as the total number of CD11b receptors, were fitted simultaneously with the model for the PK.

Simulations from the model were used to help resolve several design issues: the choice of a fixed over a mg/Kg dosing strategy, the maximum fixed dose and dose increments for a future efficacy study.