Pharmacokinetics and pharmacodynamics of the leukotriene B4 receptor antagonist CP-105,696 in man following single oral administration.
OBJECTIVE
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.
Liston
T E
TE
Department of Drug Metabolism, Pfizer Inc., Groton, CT 06340, USA.
Conklyn
M J
MJ
Houser
J
J
Wilner
K D
KD
Johnson
A
A
Apseloff
G
G
Whitacre
C
C
Showell
H J
HJ
D000284:Administration, Oral; D001578:Benzopyrans / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018845:CD11 Antigens / Q000187:drug effects / Q000378:metabolism; D018821:CD18 Antigens / Q000187:drug effects / Q000378:metabolism; D002264:Carboxylic Acids / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*
D001578:Benzopyrans; D018845:CD11 Antigens; D018821:CD18 Antigens; D002264:Carboxylic Acids; D018102:Receptors, Leukotriene B4; C089698:CP 105696