David L. Ebel

Steady‐state inhibitory activity of rofecoxib (Vioxx™) on COX‐2 versus COX‐1 was compared with that of commonly used nonsteroidal anti‐inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole‐blood assays were used to determine the effect on COX‐2 and COX‐1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX‐2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]‐induced PGE 2 generation over 8 hours on day 6 vs. baseline) was −2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX‐1 (measured as TXB 2 generation in clotting whole blood) were −5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11‐dehydro TXB 2 , a COX‐ 1‐derived product. These data support the contention that rofecoxib is the only drug of the regimens tested that uniquely inhibits COX‐2 without affecting COX‐1 .

BACKGROUND: Most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1), whose inhibition is associated with gastrointestinal ulceration, and COX-2, whose inhibition is associated with therapeutic benefits. Although agents that do not produce COX-1 activity may have fewer adverse effects, targeted disruption of the COX-2 allele in mice has resulted in severe renal problems, suggesting that COX-2 inhibition may also produce adverse effects. OBJECTIVE: To determine the effect of rofecoxib, a member of the coxib class of drugs and a specific inhibitor of the COX-2 enzyme, on renal function in elderly patients. DESIGN: A randomized, three-period, single-dose crossover study and a randomized, parallel-group, multiple-dose study. SETTING: Clinical research units. PATIENTS: 75 patients 60 to 80 years of age. INTERVENTION: In the first study, single doses of rofecoxib, 250 mg (about 5-fold to 20-fold the recommended dose); indomethacin, 75 mg; and placebo were administered to 15 patients. In the second study, multiple doses of rofecoxib, 12.5 or 25 mg/d; indomethacin, 50 mg three times daily; or placebo were administered to 60 patients. Patients in both studies received a low-sodium diet MEASUREMENTS: Glomerular filtration rate, creatinine clearance, and urinary and serum sodium and potassium values. RESULTS: Compared with placebo, single doses of rofecoxib and indomethacin decreased the glomerular filtration rate by 0.23 m/s (P < 0.001) and 0.18 mL/s (P = 0.003), respectively. In contrast, respective decreases of 0.14, 0.13, and 0.10 mL/s were observed after multiple doses of rofecoxib, 12.5 mg/d (P = 0.019); rofecoxib, 25 mg (P = 0.029), and indomethacin (P = 0.086) were administered. Changes in creatinine clearance and serum and urinary sodium and potassium were less pronounced. CONCLUSIONS: The effects of COX-2 inhibition on renal function are similar to those observed with nonselective NSAIDs. Thus, COX-2 seems to play an important role in human renal function.

In-vitro studies were conducted to assess the impact of CYP2C9 genotype on the metabolism (methyl hydroxylation) and pharmacokinetics of celecoxib, a novel cyclooxygenase-2 inhibitor and CYP2C9 substrate. When compared to cDNA-expressed wild-type CYP2C9 (CYP2C9*1), the Vmax/Km ratio for celecoxib methyl hydroxylation was reduced by 34% and 90% in the presence of recombinant CYP2C9*2 and CYP2C9*3, respectively. These data indicated that the amino acid substitution at position 359 (Ile to Leu) elicited a more pronounced effect on the metabolism of celecoxib than did a substitution at position 144 (Arg to Cys). The Vmax/Km ratio was also decreased in microsomes of livers genotyped CYP2C9*1/*2 (47% decrease, mean of two livers), or CYP2C9*1/*3 (59% decrease, one liver). In all cases, these changes were largely reflective of a decrease in Vmax, with a minimal change in Km. Based on simulations of the in-vitro data obtained with the recombinant CYP2C9 proteins, it was anticipated that the pharmacokinetics of celecoxib (as a much as a five-fold increase in plasma AUC) would be altered (versus CYP2C9*1/*1 subjects) in subjects genotyped heterozygous or homozygous for the CYP2C9*2 (Cys144) or CYP2C9*3 (Leu359) allele. In a subsequent clinical study, the AUC of celecoxib was increased (versus CYP2C9*1/*1 subjects) approximately 2.2-fold (range, 1.6-3-fold) in two CYP2C9*1/*3 subjects and one CYP2C9*3/*3 subject receiving a single oral dose (200 mg) of the drug. In contrast, there was no significant change in celecoxib AUC in two subjects genotyped CYP2C9*1/*2.

The purpose of this study was to determine the absolute bioavailability of sitagliptin, an orally active, potent and highly selective dipeptidyl peptidase-4 inhibitor recently approved in the United States for the treatment of type 2 diabetes. The effect of a high fat meal on sitagliptin pharmacokinetics was also assessed. The study was performed in two parts. Intravenous doses (2 h infusion) of 25, 50 and 100 mg were administered double-blind to 10 (8 active, 2 placebo) subjects in a fixed-sequence manner in Part I. In Part II, 12 subjects were randomized to each of three open-label treatments: an intravenous 100 mg dose; a single oral 100 mg final market image tablet administered following a high fat meal and a single oral 100 mg final market image tablet administered fasted. Following each dose, plasma and urine were collected at pre-specified times for evaluation of sitagliptin pharmacokinetics. All doses were generally well tolerated in both parts of the study. Following rising intravenous doses of sitagliptin, AUC(0-infinity) increased dose-proportionally, indicating that plasma clearance is independent of dose over the dose range evaluated. Renal clearance of unchanged sitagliptin accounted for approximately 70% of the total plasma clearance of sitagliptin, indicating that sitagliptin is primarily cleared via renal excretion. Averaged across doses, the mean total plasma clearance was 416 ml/min. The mean absolute bioavailability of sitagliptin was 87% with a 90% CI of (81%, 93%). The AUC(0-infinity) and C(max) geometric mean ratios (fed/fasted) and 90% CIs were 1.03 (0.97, 1.11) and 0.94 (0.86, 1.03), respectively, and were contained within the bounds of (0.80, 1.25). Additionally, the high-fat meal had no significant effect on T(max) or apparent terminal t(1/2). Thus, food does not affect the pharmacokinetics of sitagliptin and therefore can be administered without regard to food.