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

Content Provider	Springer Nature Link
Author	Jonsson, E. Niclas Macintyre, Fiona James, Ian Krams, Michael Marshall, Scott
Copyright Year	2005
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.
Starting Page	1236
Ending Page	1246
Page Count	11
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	22
Issue Number	8
e-ISSN	1573904X
Language	English
Publisher	Springer-Verlag
Publisher Date	2005-08-03
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	CD11b mechanistic models NONMEM pharmacodynamics pharmacokinetics stroke Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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