David L. Ebel

Metabolism And Excretion of the Dipeptidyl Peptidase 4 Inhibitor [14C]Sitagliptin in Humans

The metabolism and excretion of [14C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 μCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.

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.

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.

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.

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.

Effect of rofecoxib on the pharmacokinetics of chronically administered oral contraceptives in healthy female volunteers

The effect of rofecoxib, a highly selective cyclooxygenase (COX)‐2 inhibitor, on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET), two common components of a combination oral contraceptive product, was examined. A double‐blind, two‐period crossover study was conducted in 18 healthy women who received ORTHO‐NOVUM® 1/35, a combination of EE (35 μg) and NET (1 mg), concurrently for 14 days with either 175 mg rofecoxib or matching placebo during two consecutive menstrual cycles. Plasma was sampled for EE, NET, sex hormone binding globulin (SHBG), and albumin. The AUC0–24 h geometric mean ratio (GMR: rofecoxib/placebo) with corresponding 90% confidence interval (CI) of EE and NET was 1.13 (1.06, 1.19) and 1.18(1.13,1.24), respectively. The Cmax GMR of EE and NET was 1.06 (0.98, 1.16) and 1.04 (0.99, 1.09), respectively. In each case, the 90% CIs satisfied the predefined bioequivalence limits of (0.80, 1.25). Measures of SHBG and albumin and routine clinical and laboratory safety parameters showed no clinically meaningful changes. The addition of rofecoxib to the oral contraceptive was not associated with any clinically important changes in EE or NET pharmacokinetics and thus would not be anticipated to influence the efficacy of this contraceptive regimen.

Effect of Rofecoxib on Prednisolone and Prednisone Pharmacokinetics in Healthy Subjects

Patients receiving nonsteroidal anti‐inflammatory drug therapy may also require administration of corticosteroids, particularly patients with rheumatoid arthritis. To investigate the effect of rofecoxib on the single‐dose pharmacokinetics of oral prednisone and intravenous prednisolone, the authors conducted a randomized, double‐blind, placebo‐controlled crossover study in 12 healthy subjects. Oral rofecoxib (250.0 mg/day for 14 days) failed to influence prednisone or prednisolone pharmacokinetics after intravenous prednisolone or oral prednisone administration. The geometric mean ratio (GMR) (90% confidence interval) of prednisolone AUC∞ (rofecoxib/placebo) following intravenous and oral corticosteroid was 0.97 (0.94, 1.01) and 0.99 (0.91, 1.08), respectively. Similarly, the prednisone AUC∞ GMRs (rofecoxib/placebo) after intravenous and oral corticosteroid were 1.03 (0.95, 1.11) and 1.08 (0.92, 1.28), respectively. The absence of an effect of rofecoxib on the pharmacokinetics of oral prednisone or intravenous prednisolone indicates that no adjustment in dose of this corticosteroid is necessary when administered concurrently with rofecoxib.

Influence of Antacids on The Bioavailability (F) of A Specific Cyclooxygenase (COX)-2 Inhibitor, MK-0966 (M) in The Elderly

Clinical Pharmacology & Therapeutics (1999) 65, 173–173; doi: