HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Bridging the pharmacokinetics and pharmacodynamics of UK-279,276 across healthy volunteers and stroke patients using a mechanistically based model for target-mediated disposition.

AbstractPURPOSE:
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.
AuthorsE Niclas Jonsson, Fiona Macintyre, Ian James, Michael Krams, Scott Marshall
JournalPharmaceutical research (Pharm Res) Vol. 22 Issue 8 Pg. 1236-46 (Aug 2005) ISSN: 0724-8741 [Print] United States
PMID16078133 (Publication Type: Journal Article)
Chemical References
  • CD11b Antigen
  • CD18 Antigens
  • Glycoproteins
  • Receptors, Drug
  • UK279276
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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: