Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans.
OBJECTIVE
Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (Vioxx), characterized in vitro as a COX-2 inhibitor.


METHODS
Four panels of healthy men (n = 8 per panel) were administered rofecoxib (n = 6) (25, 100, 250, 375 mg) or placebo (n = 2) once daily on day 1 and days 3-14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time points post-dose.


RESULTS
Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9 h to 17.5 h after multiple dosing with an accumulation ratio close to 2 for all doses. COX-2 inhibitory activity as assessed by average inhibition of whole blood lipopolysaccharide-stimulated prostaglandin E2 over the 8-h post-dose period on day 14 was 0.3, 67, 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatment groups, respectively. No treatment group showed significant inhibition of COX-1 as assessed by thromboxane B2 generation in clotting whole blood. Side effects were mild and transient.


CONCLUSIONS
The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis.
Depré
M
M
Centre of Clinical Pharmacology, UZ Gasthuisberg, Leuven, Belgium. Marleen.Depre@uz.kuleuven.ac.be
Ehrich
E
E
Van Hecken
A
A
De Lepeleire
I
I
Dallob
A
A
Wong
P
P
Porras
A
A
Gertz
B J
BJ
De Schepper
P J
PJ
D000328:Adult; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000187:drug effects; D007783:Lactones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D008297:Male; D008565:Membrane Proteins; D008657:Metabolic Clearance Rate; D010919:Placebos; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D013450:Sulfones; D013929:Thromboxane B2 / Q000097:blood
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D010919:Placebos; D013450:Sulfones; C116926:rofecoxib; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone