Jutta Miller

Dose proportionality of oral etoricoxib, a highly selective cyclooxygenase-2 inhibitor, in healthy volunteers.

To assess dose proportionality of etoricoxib across the anticipated clinical dose range, a single panel of 12 healthy subjects was administered single oral doses of etoricoxib of 5,10, 20, 40, and 120 mg in an open, two‐part, five‐period crossover study. Plasma samples were collected after each dose and analyzed for etoricoxib concentrations. The pharmacokinetics of etoricoxib appear to be linear over the entire dose range examined, from 5 to 120 mg. Etoricoxib was found to be well tolerated across the 5 to 120 mg dose range.

Comparative inhibitory activity of etoricoxib, celecoxib, and diclofenac on COX-2 versus COX-1 in healthy subjects.

We determined cyclo‐oxygenase‐1 and cyclo‐oxygenase‐2 inhibition in healthy middle‐aged subjects (41–65 years) randomly assigned to four 7‐day treatment sequences of etoricoxib 90 mg every day, celecoxib 200 mg twice a day, diclofenac 75 mg twice a day, or placebo in a double‐blind, randomized, 4‐period crossover study. Maximum inhibition of thromboxane B2 (cyclo‐oxygenase‐1 activity) in clotting whole blood on day 7 (0–24 hours postdose) was the primary endpoint. Inhibition of lipopolysaccharide‐induced prostaglandin E2 in whole blood (cyclo‐oxygenase‐2 activity) was assessed on day 7 (0–24 hours postdose) as a secondary endpoint. Diclofenac had significantly greater maximum inhibition of thromboxane B2 versus each comparator (P < .001); placebo 2.4% (95% confidence interval: −8.7% to 12.3%), diclofenac 92.2% (91.4% to 92.9%), etoricoxib 15.5% (6.6% to 23.5%), and celecoxib 20.2% (11.5% to 28.1%). Prostaglandin E2 synthesis was inhibited with a rank order of potency of diclofenac > etoricoxib > celecoxib. In summary, at doses commonly used in rheumatoid arthritis, diclofenac significantly inhibits both cyclo‐oxygenase‐1 and cyclo‐oxygenase‐2, whereas etoricoxib and celecoxib significantly inhibit cyclo‐oxygenase‐2 and do not substantially inhibit cyclo‐oxygenase‐1.

Individual and Combined Effects of Peroxisome Proliferator-Activated Receptor α and γ Agonists, Fenofibrate and Rosiglitazone, on Biomarkers of Lipid and Glucose Metabolism in Healthy Nondiabetic Volunteers

This open‐label, randomized, placebo‐controlled, incomplete‐block, 3‐period crossover pilot study investigated the effects of peroxisome proliferator‐activated receptor α‐ and γ‐agonists on biomarkers of lipid and glucose metabolism in 12 nondiabetic subjects. Plasma samples were collected before and after each 14‐day treatment with placebo, fenofibrate (201 mg/d), rosiglitazone (4 mg twice daily), and combined fenofibrate (201 mg/d) plus rosiglitazone (4 mg twice daily). Except for triglycerides (P < .042) and free fatty acids (P <.074), no significant interaction was demonstrated between fenofibrate and rosiglitazone; thus, the effect due to each drug alone was evaluated (presence/absence of drug). Fenofibrate significantly (P < .050) increased lipoprotein lipase activity (35%) and decreased apolipoproteins B (13%) and C‐III (20%). Rosiglitazone significantly (P < .050) decreased fasting glucose (7.3%) and increased apolipoprotein C‐III (19%) and adiponectin (137%). Fenofibrate and rosiglitazone also produced effects on triglyoerides and free fatty acids, but it was not possible to determine if these effects were synergistic in nature.

A Thorough QTc Study to Assess the Effect of Sitagliptin, a DPP4 Inhibitor, on Ventricular Repolarization in Healthy Subjects

A randomized, double‐blind, placebo‐controlled, 4‐period crossover study was performed with a single oral dose of sitagliptin (100 mg, 800 mg), moxifloxacin (400 mg), and placebo in order to provide a rigorous assessment of the effect of sitagliptin on ventricular repolarization based on the ICH E14 guidance. The clinical dose of sitagliptin 100 mg was not associated with an increase in QTc interval, corrected using the Fridericia correction (QTcf), at any time point. The supratherapeutic 800‐mg dose of sitagliptin was generally well tolerated and was associated with minimal, clinically insignificant prolongation of the QTcf interval at concentrations approximately 11‐fold higher than maximal concentrations following the 100‐mg clinical dose. The PK/QTc model demonstrated a shallow relationship between the plasma concentration of sitagliptin and the placebo‐subtracted QTcf change from baseline, with a 0.59‐millisecond increase in QTc for every 1000‐nM increment in sitagliptin plasma concentration. The sensitivity of the assay to detect modest increases in QTc interval was established with the active control moxifloxacin. In conclusion, at clinically relevant concentrations, sitagliptin is not associated with clinically meaningful QTcf prolongation.

Effects of Etoricoxib and Comparator Nonsteroidal Anti-Inflammatory Drugs on Urinary Sodium Excretion, Blood Pressure, and Other Renal Function Indicators in Elderly Subjects Consuming a Controlled Sodium Diet

This multicenter, double‐blind, randomized, placebo‐controlled, parallel‐group study assessed renal function during dosing with etoricoxib 90 mg daily, celecoxib 200 mg twice daily, and naproxen 500 mg twice daily. Male and female subjects 60 to 81 years old (n = 85), in sodium balance on a controlled, normal sodium diet, were treated for 15 days. There were no clinically meaningful between‐treatment differences in urinary sodium excretion, creatinine clearance, body weight, or serum electrolytes during the 2 weeks of treatment. Etoricoxib and celecoxib had no effect on the urinary thromboxane metabolite, 11‐dehydrothromboxane B2, while significantly decreasing the urinary prostacyclin metabolite, 2,3‐dinor‐6‐keto PGF1α. Decreases were greater for both metabolites following naproxen. Ambulatory systolic blood pressures were significantly higher than placebo for all treatments, with moderately greater increases for etoricoxib relative to other active treatments on day 14. Ambulatory diastolic blood pressures were significantly higher than placebo for etoricoxib and naproxen but not for celecoxib.

PI-65The effect of MK-0431 on the pharmacokinetics of digoxin after concomitant administration for 10 days in healthy subjects

MK‐0431 (sitagliptin) is a highly selective DPP‐IV inhibitor being developed for the treatment of type 2 diabetes. The purpose of this study was to assess the effect of sitagliptin (SIT) on the pharmacokinetics (PK) of digoxin (DIG) after co‐administration.

A Dual PPAR α/γ Agonist Increases Adiponectin and Improves Plasma Lipid Profiles in Healthy Subjects

AbstractBackground: The objective of these studies was to evaluate the pharmacokinetics and pharmacodynamics of MK-0767, a prototypical dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist, following administration of single and multiple oral doses in healthy male subjects. Methods: The first study was a double-blind, randomised, placebo-controlled, alternating two-panel, rising dose protocol in which single doses of l–80mg of MK-0767 were administered. The second study was a double-blind, randomised, placebo-controlled, staggered incremental dose, parallel-group protocol in which multiple doses of 0.3–25mg of MK-0767 were administered once daily for 14 days. In both studies at each dose level, six subjects received MK-0767 and two subjects received placebo. Results: Plasma area under the concentration-time curve and maximum plasma concentration increased with single and multiple doses of MK-0767 over the dose ranges studied. The apparent terminal half-life of MK-0767 averaged ≈36 hours following single and multiple doses. Steady-state plasma concentrations were achieved following ≈8 days of multiple doses. Compared with placebo, MK-0767 produced dose-dependent reductions in triglycerides (−26 ± 8% [p = 0.002] and −33 ± 13% [p = 0.008]) and free fatty acids (−50 ± 11% [p < 0.001] and −67 ± 23% [p = 0.008]) following single and multiple doses, respectively. Significant (p < 0.050) dose-dependent alterations in adiponectin (332 ± 36%), low-density lipoprotein cholesterol (−29 ± 5%), total cholesterol (−19 ± 3%), non-high-density lipoprotein cholesterol (−28 ± 4%), and fasting plasma glucose (−6 ± 2%; only in the 25mg group) were observed after multiple doses. Conclusions: The observed effects of MK-0767 on adiponectin, free fatty acids and lipids, even after single doses, demonstrate that this prototypical dual PPAR α/γ agonist has clinically meaningful activity in vivo.

The Effects of Modifying In Vivo Cytochrome P450 3A (CYP3A) Activity on Etoricoxib Pharmacokinetics and of Etoricoxib Administration on CYP3A Activity

To investigate the influence of modifying in vivo cytochrome P450 3A (CYP3A) activity on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase‐2, and of etoricoxib administration on CYP3A activity, a 3‐part, randomized, crossover study was conducted in 3 panels of healthy volunteers. In part I, 8 subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 400 mg ketoconazole, a known strong inhibitor of CYP3A. In part II, 8 different subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 600 mg rifampin, a known strong inducer of CYP3A. In parts I and II, plasma samples were collected following each etoricoxib dose and analyzed for etoricoxib. In part III, 8 different subjects were administered 120 mg etoricoxib or placebo once daily for 11 days, and the erythromycin breath test was administered on day 11 of each period. Coadministration of etoricoxib with daily doses of ketoconazole resulted in an average 43% increase in etoricoxib AUC; based on previous studies, this increase would not be expected to have any clinically meaningful effect. In contrast, coadministration of etoricoxib with daily doses of rifampin had a potentially clinically important effect on etoricoxib pharmacokinetics (average 65% decrease in etoricoxib AUC). Etoricoxib had no effect on hepatic CYP3A activity, as assessed by the erythromycin breath test.

Bioequivalence of Sitagliptin/Metformin Fixed-Dose Combination Tablets and Concomitant Administration of Sitagliptin and Metformin in Healthy Adult Subjects

AbstractBackground: Treatment with an oral antihyperglycaemic agent administered as monotherapy is often unsuccessful at achieving or maintaining glycaemic control in patients with type 2 diabetes mellitus. The combined use of sitagliptin and metformin is an effective treatment for type 2 diabetes mellitus, consistent with the complementary mechanisms of action by which these two agents improve glucose control. Objectives: To establish bioequivalence between sitagliptin/metformin fixeddose combination (FDC) tablets (Janumet®) and co-administration of corresponding doses of sitagliptin and metformin as individual tablets. Methods: This was an randomized, open-label, two-part, two-period crossover study, which included a total of 48 healthy subjects, 24 subjects per part (parts I and II). Within each part, subjects were assigned to receive treatments in random order; treatment periods were separated by a washout interval of at least 7 days. Eligible study participants included healthy, non-smoking (within previous 6 months), male and female subjects aged between 18 and 45 years with a body mass index ≤32kg/m2. Part I consisted of treatments A (co-administration of sitagliptin 50 mg and metformin 500 mg) and B (sitagliptin/metformin 50mg/500mg FDC tablet); part II consisted of treatments C (co-administration of sitagliptin 50 mg and metformin 1000 mg) and D (sitagliptin 50 mg/metformin 1000 mg FDC tablet). Blood samples were collected pre-dose and up to 72 hours post-dose in each treatment period for determination of plasma sitagliptin and metformin concentrations and calculation of the respective pharmacokinetic parameters.The area under the plasma concentration-time curve from time zero to infinity (AUC∞) and the maximum plasma concentration (Cmax) for both sitagliptin and metformin were designated as the primary and secondary study endpoints, respectively, and analysed using an ANOVA model after logarithmic transformation of the data. Bioequivalence was established if the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs; FDC tablet/co-administration) of the AUC∞ and Cmax for both sitagliptin and metformin fell within pre-specified bounds of (0.80, 1.25). Results: The GMRs (90% CI) for the AUC∞ of sitagliptin 50 mg and metformin 500 mg were 0.98 (0.96, 1.00) and 1.0 (0.95, 1.04), respectively, and for Cmax of sitagliptin and metformin were 1.00 (0.94, 1.06) and 1.00 (0.94, 1.06), respectively. The GMRs (90% CI) for the AUC∞ of sitagliptin 50 mg and metformin 1000 mg (part II) were 0.97 (0.95, 0.99) and 1.00 (0.94, 1.07), respectively, and for the Cmax of sitagliptin and metformin were 0.94 (0.88, 1.01) and 1.01 (0.93, 1.10), respectively. In both part I and part II, the 90% CIs of the GMRs of the AUC∞ and Cmax for both sitagliptin and metformin all fell within the pre-specified bioequivalence bounds of (0.80, 1.25). Administration of single doses of sitagliptin/metformin 50 mg/500 mg (part I) and 50 mg/1000 mg FDC tablets (part II) and co-administration of corresponding doses of sitagliptin and metformin as individual tablets were generally well tolerated. Conclusion: The sitagliptin/metformin 50 mg/500 mg and 50 mg/1000 mg FDC tablets are bioequivalent to co-administration of corresponding doses of sitagliptin and metformin as individual tablets and support bioequivalence to the sitagliptin/metformin 50 mg/850 mg tablet strength. These results indicate that the safety and efficacy profile of co-administration of sitagliptin and metformin can be extended to the sitagliptin/metformin FDC tablets.

Sitagliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Does Not Affect the Pharmacokinetics of Ethinyl Estradiol or Norethindrone in Healthy Female Subjects

Sitagliptin is a dipeptidyl peptidase‐IV (DPP‐4) inhibitor used for the treatment of patients with type 2 diabetes mellitus. This randomized, placebo‐controlled, 2‐period, crossover study evaluated the effect of sitagliptin on the pharmacokinetics of 17 α‐ethinyl estradiol (EE2) and norethindrone (NET) in healthy female subjects who were receiving oral contraceptives for >3 months prior to enrollment. A total of 18 subjects with normal menstrual cycles received the oral contraceptive pill ORTHO‐NOVUM® 7/7/7 on days 1 to 28 for 2 successive cycles, and on days 1 to 21 were randomly assigned to receive sitagliptin 200 mg/day (2 × 100 mg tablets) or placebo using a computer‐generated allocation schedule. Blood samples for determination of plasma EE2 and NET concentrations were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose on day 20 or 21 of each treatment period. The GMRs (90% confidence interval [CI]) for the AUC0–24hr of EE2 and NET were 0.99 (0.93, 1.06) and 1.03 (0.97, 1.09), respectively, and for Cmax were 0.97 (0.86, 1.10) and 0.98 (0.89, 1.07), respectively. The coadministration of sitagliptin 200 mg/day with an oral contraceptive for 21 days did not lead to clinically meaningful alterations in the pharmacokinetics of EE2 and NET.