Marina De Smet

Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses.

Sitagliptin (MK‐0431 [(2R)‐4‐oxo‐4‐(3‐[trifluoromethyl]‐5,6‐dihydro[1,2,4]triazolo[4,3‐a]pyrazin‐7[8H]‐yl)‐1‐(2,4,5‐trifluorophenyl)butan‐2‐amine]) is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP‐IV) currently in phase III development for the treatment of type 2 diabetes.

Prevention of cisplatin-induced acute and delayed emesis by the selective neurokinin-1 antagonists, L-758,298 and MK-869 - A randomized controlled trial.

Recent studies have suggested that antiemetic therapy with a triple combination of the neurokinin‐1 receptor antagonist MK‐869, a serotonin (5‐HT3) antagonist, and dexamethasone provides enhanced control of cisplatin‐induced emesis compared with standard therapy regimens. The authors compared the antiemetic activity of a dual combination of MK‐869 and dexamethasone with that of a standard dual combination of ondansetron and dexamethasone to characterize further the efficacy and tolerability profile of MK‐869.

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.

Effect of Sitagliptin on the Pharmacokinetics of Simvastatin

P atients with type 2 diabetes are at an increased risk for cardiovascular morbidity and mortality. Treatment with HMG-CoA reductase inhibitors (statins) reduces the risk of cardiovascular events in patients with diabetes. Treatment guidelines consider diabetes as a coronary heart disease risk equivalent and recommend statin therapy for patients with diabetes. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral antihyperglycemic agents. Sitagliptin, a highly selective DPP-4 inhibitor, is available in many countries for the treatment of patients with type 2 diabetes. Because sitagliptin and a statin may be commonly administered to patients with type 2 diabetes, the potential for sitagliptin to alter the pharmacokinetics of simvastatin, a CYP3A4 substrate, was evaluated in this study. The metabolism of simvastatin is complex, resulting in the generation of multiple active and inactive metabolites. Active HMG-CoA reductase inhibitors represent the total pool of pharmacologically active species in plasma following simvastatin administration (ie, simvastatin acid and other active metabolites). Therefore, assessment of the AUC0-last for active HMGCoA reductase inhibitors was the primary endpoint in this study. The pharmacokinetic parameters for simvastatin (lactone; pharmacologically inactive), simvastatin acid (active), and total HMG-CoA reductase inhibitors were secondary endpoints in this study.

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.

Evaluation of the pharmacokinetics of digoxin in healthy subjects receiving etoricoxib

AIMS Digoxin is a commonly prescribed cardiac glycoside with a narrow therapeutic index. The aim was to investigate whether the cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug etoricoxib affects the steady-state pharmacokinetics of digoxin. METHODS This was a double-blind, randomized, placebo-controlled, two-period cross-over study. In each period, 14 healthy volunteers ranging in age from 21 to 35 years received oral digoxin 0.25 mg daily and were randomized to either etoricoxib 120 mg or matching placebo tablets once daily for 10 days. Trough digoxin plasma concentrations were analysed by linear regression to examine digoxin accumulation over time. RESULTS The geometric mean ratios (etoricoxib/placebo) for AUC(0-24h), C(max) and urinary excretion were 1.06 (90% confidence interval 0.97, 1.17), 1.33 (1.21, 1.46) and 1.10 (1.00, 1.20), respectively. The median (range) for digoxin T(max) (h) values with etoricoxib and placebo were 0.5 (0.5, 1.5) and 1.0 (0.5, 1.5), respectively. Steady-state digoxin plasma concentrations were achieved by day 7 in each treatment period. No serious adverse experiences were reported. CONCLUSIONS Although etoricoxib 120 mg did produce an approximately 33% increase in digoxin C(max), this increase does not appear to be clinically meaningful, as cardiotoxicity with digoxin has been associated with elevations in steady-state rather than peak concentrations. From these results, it appears that etoricoxib does not cause any changes in digoxin steady-state pharmacokinetics that would necessitate a dose adjustment.