Abstract | PURPOSE:
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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Authors | E Niclas Jonsson, Fiona Macintyre, Ian James, Michael Krams, Scott Marshall |
Journal | Pharmaceutical research
(Pharm Res)
Vol. 22
Issue 8
Pg. 1236-46
(Aug 2005)
ISSN: 0724-8741 [Print] United States |
PMID | 16078133
(Publication Type: Journal Article)
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Chemical References |
- CD11b Antigen
- CD18 Antigens
- Glycoproteins
- Receptors, Drug
- UK279276
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Topics |
- CD11b Antigen
(metabolism)
- CD18 Antigens
(metabolism)
- Fluorescent Antibody Technique
- Glycoproteins
(pharmacokinetics, therapeutic use)
- Half-Life
- Humans
- Kinetics
- Leukocyte Count
- Mitosis
- Models, Statistical
- Neutrophils
(drug effects, metabolism)
- Receptors, Drug
(drug effects)
- Stroke
(drug therapy, metabolism)
- Tissue Distribution
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