Pharmacokinetics and pharmacodynamics of the leukotriene B4 receptor antagonist CP-105,696 in man following single oral administration

Br J Clin Pharmacol. 1998 Feb;45(2):115-21. doi: 10.1046/j.1365-2125.1998.00646.x.


Aims: CP-105,696, (+)-1-(3S,4R)-[3-(4-phenylbenzyl)-4-hydroxy-chroman-7-yl] cyclopropane carboxylic acid is a potent, novel LTB4 receptor antagonist advanced to clinical trials to determine its efficacy in inflammatory diseases. The pharmacokinetics and pharmacodynamics of CP-105,696 were investigated in healthy male volunteers following oral administration of single doses of 5 to 640 mg.

Methods: Forty-eight subjects participated in a randomized, double-blind, parallel group study. Plasma and urine concentrations of CP-105,696 were determined at intervals after drug administration. As an indication of LTB4 receptor antagonism following oral administration of CP-105,696, the inhibiton of LTB4-induced upregulation of the neutrophil cell surface complement receptor (CR3), CD11b/CD18, was monitored at 4 h following drug administration using an ex vivo whole blood flow cytometry assay.

Results: Cmax and AUC(0, infinity) increased in a dose-related manner. Respective mean Cmax values were 0.54 to 30.41 microg ml(-1) following doses of 5 to 640 mg. Respective mean AUC(0, infinity) values were 1337 to 16819 microg ml(-1) h for the 40 to 640 mg dose groups. Plasma concentrations declined in a monoexponential manner, with terminal elimination half-lives ranging from 289 to 495 h. Group mean terminal elimination half-lives were dose-independent. Urinary excretion of unchanged drug accounted for < 1% of the administered dose. A linear relationship was observed between CP-105,696 plasma concentrations and inhibition of LTB4-mediated CD11b upregulation on human neutrophils in whole blood. CP-105,696 plasma concentrations of 5-6 microg ml(-1) were necessary to elicit a two-fold shift to the right of the LTB4 concentration response curve for CD11b upregulation.

Conclusions: These studies demonstrate pharmacologically significant LTB4-receptor antagonism following a single dose of CP-105,696 and pharmacokinetics consistent with once-daily dosing.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Benzopyrans / blood
  • Benzopyrans / pharmacokinetics*
  • Benzopyrans / pharmacology*
  • CD11 Antigens / drug effects
  • CD11 Antigens / metabolism
  • CD18 Antigens / drug effects
  • CD18 Antigens / metabolism
  • Carboxylic Acids / blood
  • Carboxylic Acids / pharmacokinetics*
  • Carboxylic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Humans
  • Male
  • Receptors, Leukotriene B4 / antagonists & inhibitors*


  • Benzopyrans
  • CD11 Antigens
  • CD18 Antigens
  • Carboxylic Acids
  • Receptors, Leukotriene B4
  • CP 105696