Jules I. Schwartz

Cyclooxygenase‐2 inhibition by rofecoxib reverses naturally occurring fever in humans

Cyclooxygenase (COX) exists as constitutive (COX‐1) and inducible (COX‐2) isoforms. Nonsteroidal anti‐inflammatory drugs (NSAIDs) such as ibuprofen and diclofenac inhibit both COX‐1 and COX‐2. The role of COX‐2 in the genesis of fever in monkeys and humans was examined with use of the specific COX‐2 inhibitor rofecoxib. Rofecoxib was administered to monkeys made febrile by 6 μg/kg intravenous lipopolysaccharide. Induced pyrexia was followed by oral rofecoxib (1 or 3 mg/kg), diclofenac (3 mg/kg), or vehicle. Rofecoxib and diclofenac rapidly reversed the elevated temperature (P < .05 versus vehicle for 3 mg/kg rofecoxib and diclofenac at 70 to 90 minutes after dosing). A single‐dose, parallel‐group, double‐blind randomized trial was conducted in 94 patients with fever caused by a viral‐type illness. Mean baseline temperature was similar for all groups (~38.5°C). Patients received oral doses of 12.5 mg rofecoxib, 25 mg rofecoxib, 400 mg ibuprofen, or placebo and the mean ± SE change in oral temperature at 4 hours after dosing was −0.97°C ± 0.11°C, −1.19°C ± 0.09°C, −1.20°C ± 0.11°C, and 0.01°C ± 0.17°C, respectively (P < .001 for active treatments versus placebo). Specific inhibition of COX‐2 by rofecoxib results in antipyretic activity in monkeys and humans comparable to dual COX‐1/COX‐2 inhibitors such as diclofenac or ibuprofen. The data support the hypothesis that it is the COX‐2 isoform that is primarily involved in the genesis of fever in humans.

The effect of rofecoxib on the pharmacodynamics and pharmacokinetics of warfarin

The objective of this study was to examine the effect of 3 doses of rofecoxib (12.5, 25, and 50 mg) on the pharmacodynamics and pharmacokinetics of warfarin.

The Effect of Erythromycin on the Disposition Kinetics of Warfarin

Erythromycin is generally regarded as innocuous in regard to adverse interactions with other drugs. Recently, however, its potentiation of theophylline and warfarin has been reported. The present investigation defined more specifically the kinetics of the interaction between erythromycin and warfarin. Warfarin kinetics were evaluated in 12 normal subjects who took a single 1 mg/kg dose of warfarin with and without erythromycin. Erythromycin (250 mg p.o.) every 6 h for 8 days decreased warfarin clearance by 14% (p less than 0.001). Warfarins apparent volume of distribution was not affected. Further, the effect of erythromycin was greatest among subjects whose control phase warfarin clearance was relatively slow, and least among those whose control phase warfarin clearance was relatively fast. The magnitude of the decrease in warfarin clearance correlated negatively with control warfarin clearance (r = -0.89, p less than 0.005). These data are consistent with the interpretation that erythromycin can potentiate warfarin-induced hypoprothrombinemia by slowing warfarin clearance.

Lack of Pharmacokinetic Interaction between Rofecoxib and Methotrexate in Rheumatoid Arthritis Patients

Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase‐2 (COX‐2). Methotrexate is a disease‐modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double‐blind, placebo‐controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days‐1, 7,14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days1 to 21 only to maintain a double‐blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7‐hydroxymethotrexate. The AUC00–∞ geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day −1, day 14/day‐1, and day 21/day −1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day −1). All AUC0–∞ GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7‐hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.

An evaluation of the dose-dependent inhibition of CYP1A2 by rofecoxib using theophylline as a CYP1A2 probe.

This study was undertaken to determine whether rofecoxib can interfere with CYP1A2 activity in humans using theophylline as a probe substrate. Single oral doses of theophylline were administered to each of three panels of 12 healthy subjects receiving daily doses of rofecoxib for 7 days to examine the effect of rofecoxib administration on the absorption and disposition of theophylline. Each panel was administered doses of 12.5, 25, or 50 mg of rofecoxib or a matching placebo in a two‐way, randomized, crossover fashion and administered a single oral 300‐mg dose of theophylline on day 7 of rofecoxib or placebo administration. Plasma concentrations of theophylline were monitored for 48 hours postdose to assess differences in pharmacokinetics. All three commercially marketed doses of rofecoxib were found to slow the clearance of theophylline with no detectable effect on absorption. CL/F values for theophylline were estimated from AUC∞ and by point estimates from the concentrations of drug in plasma at 12 and 24 hours postdose. The point estimates of CL/F were found to be in agreement with those derived from AUC.

Effect of montelukast on single-dose theophylline pharmacokinetics.

The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist in development for treatment of asthma, on single-dose theophylline plasma concentrations was studied in three separate clinical trials. Montelukast was evaluated at 10 mg once daily (the clinical dosage), 200 mg once daily, and 600 mg (200 mg three times daily). At the clinical dosage, montelukast did not change single-dose theophylline plasma concentration in a clinically important manner. The geometric mean ratios for theophylline area under the plasma concentration versus time curve (AUC0) (0.92) and maximal plasma concentration (Cmax) (1.04) were well within the predefined and generally accepted bioequivalence range of 0.80 and 1.25. Montelukast decreased theophylline Cmax by 12% and 10%, AUC0 by 43% and 44%, and elimination half-time by 44% and 39% at 200 mg/d (oral and intravenous, respectively), and at 600 mg/d, montelukast decreased theophylline Cmax by 25%, AUC0 by 66%, and elimination half-time by 63%. These results show that montelukast at the clinical dosage did not change theophylline pharmacokinetics in a clinically important manner, but at 20− to 60-fold higher dosages, montelukast significantly reduced the theophylline pharmacokinetics parameters; an apparent dosage dependence is suggested.

Theophylline kinetics: dose dependency and single sample prediction of clearance

Theophylline clearance was measured at 3 doses (2, 4 and 6 mg/kg) in 10 young, healthy adult subjects. Clearance decreased as the dose of theophylline increased going from 0.064 +/- 0.016 to 0.052 +/- 0.011 1.h-1.kg-1 at the 2 and 6 mg/kg doses, respectively (p less than 0.02). A simplified method for estimating theophylline clearance was tested using single plasma concentrations of theophylline and assuming a constant value (0.5 l/kg) for volume distribution of theophylline. This method gave the best results when samples were drawn at 12 or 24 h after a 2 or 4 mg/kg intravenous dose of theophylline, respectively, and was effectively applied in estimating the quantitative impact of cimetidine administration on theophylline clearance.

Examination of the Effect of Increasing Doses of Etoricoxib on Oral Methotrexate Pharmacokinetics in Patients With Rheumatoid Arthritis

The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5–20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1–7) and then 120 mg (days 8–14); in study 2, patients received etoricoxib 90 mg (days 1–7) and then 120 mg (days 8–14). For study 1, the AUC0‐∞ geometric mean ratio (GMR) (90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration‐time curve from zero to infinity (AUC0‐∞) GMR (90% CI) for day 14 was 1.28 (1.15, 1.42) for etoricoxib 120 mg. For study 2, the AUC0‐∞ GMR (90% CI) for day 7 versus baseline was 1.07 (1.01, 1.13) for etoricoxib 90 mg; the AUC0‐∞ GMR (90% CI) for day 14 was 1.05 (0.99, 1.11) for etoricoxib 120 mg. In summary, etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations. Although no effect on methotrexate pharmacokinetics was observed with etoricoxib 120 mg in study 2, GMR AUC0‐∞ fell outside the prespecified bounds in study 1. Standard monitoring of methotrexate‐related toxicity should be continued when etoricoxib and methotrexate are administered concurrently, especially with doses >90 mg etoricoxib.

The Effect of Etoricoxib on the Pharmacodynamics and Pharmacokinetics of Warfarin

The effects of etoricoxib on pharmacodynamic and pharmacokinetic parameters of warfarin were determined in healthy men and women. Subjects titrated with warfarin to an international normalized ratio for prothrombin time of 1.4 to 1.7 during a 28‐day prestudy period were randomly assigned in crossover fashion to be coadministered etoricoxib (120 mg) or matching placebo over two 21‐day continuous periods. On day 21, a 24‐hour pharmacokinetic profile of both S(−) and R(+) warfarin, as well as international normalized ratio values, were determined. Etoricoxib increased the international normalized ratio by 13% (90% confidence interval: 8%, 19%; P ≤.001). Etoricoxib had no effect on the pharmacokinetics of S(−) warfarin but led to a modest increase in the AUC24 h (∼10%) of R(+) warfarin. This increase in the international normalized ratio is not likely to be clinically important in most patients; however, the international normalized ratio of patients coadministered oral anticoagulants and etoricoxib should be closely monitored, particularly during initiation of therapy.

Effect of rofecoxib on the pharmacokinetics of digoxin in healthy volunteers

The authors examined the effect of the cyclooxygenase‐2 (COX‐2) inhibitor, rofecoxib, at steady state on the pharmacokinetics of digoxin following a single dose in healthy subjects. Each healthy subject (N = 10) received rofecoxib (75 mg once daily) or placebo for 11 daysina double‐blind, randomized, balanced, two‐period crossover study. A single 0.5 mg oral dose of digoxin elixir was administered on the 7th day of each 11‐day period. Each treatment period was separated by 14 to 21 days. Samples for plasma and urine immunoreactive digoxin concentrations were collected through 120hours following the digoxin dose. No statistically significant differences between treatment groups were observed for any of the calculated digoxin pharmacokinetic parameters. For digoxin AUC(0‐∞), AUC(0–24), and Cmax, the geometric mean ratios (90% confidence interval) for (rofecoxib + digoxin/placebo + digoxin) were 1.04 (0.94, 1.14), 1.02 (0.94, 1.09), and 1.00 (0.91, 1.10), respectively. The digoxin median tmax was 0.5 hours for both treatments. The harmonic mean elimination half‐life was 45.7 and 43.4 hours for rofecoxib + digoxin and placebo + digoxin treatments, respectively. Digoxin is eliminated renally. The mean (SD) cumulative urinary excretion of immunoreactive digoxin after concurrent treatment with rofecoxib or placebo was 228.2 (± 30.8) and 235.1 (± 39.1) μg/120 hours, respectively. Transient and minor adverse events occurred with similar frequency on placebo and rofecoxib treatments, and no treatment‐related pattern was apparent. Rofecoxib did not influence the plasma pharmacokinetics or renal elimination of a single oral dose of digoxin.