Single-dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

AIMS: Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. METHODS: Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. RESULTS: Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. CONCLUSIONS: Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.

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 B(2) (cyclo-oxygenase-1 activity) in clotting whole blood on day 7 (0-24 hours postdose) was the primary endpoint. Inhibition of lipopolysaccharide-induced prostaglandin E(2) 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 B(2) 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 E(2) 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.

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 B(2), while significantly decreasing the urinary prostacyclin metabolite, 2,3-dinor-6-keto PGF(1alpha). 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.

Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes.

CONTEXT: In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral antihyperglycemic agents in development for the treatment of type 2 diabetes. The degree of DPP-4 inhibition and the level of active incretin augmentation required for glucose lowering efficacy after an oral glucose tolerance test (OGTT) were evaluated. OBJECTIVE: The objective of the study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of sitagliptin. DESIGN: This was a randomized, double-blind, placebo-controlled, three-period, single-dose crossover study. SETTING: The study was conducted at six investigational sites. PATIENTS: The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents. INTERVENTIONS: Interventions included sitagliptin 25 mg, sitagliptin 200 mg, or placebo. MAIN OUTCOME MEASURES: Measurements included plasma DPP-4 activity; post-OGTT glucose excursion; active and total incretin GIP levels; insulin, C-peptide, and glucagon concentrations; and sitagliptin pharmacokinetics. RESULTS: Sitagliptin dose-dependently inhibited plasma DPP-4 activity over 24 h, enhanced active GLP-1 and GIP levels, increased insulin/C-peptide, decreased glucagon, and reduced glycemic excursion after OGTTs administered at 2 and 24 h after single oral 25- or 200-mg doses of sitagliptin. Sitagliptin was generally well tolerated, with no hypoglycemic events. CONCLUSIONS: In this study in patients with type 2 diabetes, near maximal glucose-lowering efficacy of sitagliptin after single oral doses was associated with inhibition of plasma DPP-4 activity of 80% or greater, corresponding to a plasma sitagliptin concentration of 100 nm or greater, and an augmentation of active GLP-1 and GIP levels of 2-fold or higher after an OGTT.

Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects.

Sitagliptin (MK-0431) is an oral, potent, and selective dipeptidyl peptidase-IV (DPP-4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double-blind, placebo-controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle-aged (45-63 years), nondiabetic, obese (body mass index: 30-40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady-state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to approximately 90% inhibition of plasma DPP-4 activity, increased active glucagon-like peptide-1 (GLP-1) levels by 2.7-fold (P < .001), and decreased post-oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP-4 activity, increased active GLP-1, and reduced glycemic excursion.

Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers.

BACKGROUND: Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a new class of oral antihyperglycemic agents. Sitagliptin is an orally active and selective DPP-IV inhibitor currently in Phase III development for the treatment of type 2 diabetes mellitus. OBJECTIVE: The aim of this study was to assess the pharmacokinetic and pharmacodynamic (PK/PD) properties and tolerability of multiple oral once-daily or twice-daily doses of sitagliptin. METHODS: This double-blind, randomized, placebo-controlled,incremental oral-dose study was conducted at SGS Biopharma, Antwerp, Belgium. Healthy, nonsmoking male volunteers aged 18 to 45 years with a creatinine clearance rate of >80 mL/min and normoglycemia and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 8 treatment groups: sitagliptin 25, 50, 100, 200, or 400 mg or placebo, QD for 10 days; a single dose of sitagliptin 800 mg administered on day 1 followed by 600 mg QD on days 3 to 10; or sitagliptin 300 mg BID for 10 days. For analysis of PK properties, plasma and urine samples were obtained before study drug administration on day 1 and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 16 hours after study drug administration on day 1; before study drug administration on days 2 to 9; and every 24 hours for 96 hours after the last dose on day 10, and analyzed for sitagliptin concentrations. Assays were used to measure inhibition of plasma DPP-IV activity and plasma concentrations of active and total glucagon-like peptide-1 (GLP-1), glucose, and glucagon, and serum concentrations of insulin, C-peptide, insulin-like growth factor-1, and insulin like growth factor binding protein-3. Tolerability was assessed throughout the study using physical examination, including vital sign measurements; 12-lead electrocardiography; and laboratory analysis, including hematology, biochemistry (hepatic aminotransferase and creatine phosphokinase), and urinalysis. RESULTS: Seventy subjects were enrolled (mean age, 32.9 years [range, 18-45 years]; mean weight, 79.7 kg [range, 63.4-97.7 kg]; 8 patients per sitagliptin study group and 14 patients in the control group). In the sitagliptin groups, the plasma concentration-time profiles and principal PK parameters (T(max), C(max), and t((1/2))) were statistically similar at days 1 (single dose) and 10 (steady state). In the groups receiving sitagliptin QD doses, accumulation of sitagliptin was modest (AUC accumulation ratio [day 10/day 1] range, 1.05-1.29), and the apparent terminal elimination t((1/2)) was 11.8 to 14.4 hours. At steady state in the sitagliptin QD groups, the mean proportion of drug excreted unchanged in the urine was approximately 70.6%. Dose-dependent inhibition of plasma DPP-IV activity was apparent, and the pattern of inhibition at steady state (day 10) was statistically similar to that observed on day 1. Day-10 weighted mean inhibition of plasma DPP-IV activity over 24 hours was > or = 80% for doses of > or = 50 mg QD. After a standard meal, active GLP-1 concentrations were significantly increased in the sitagliptin groups by approximately 2-fold compared with that in the control group, a finding consistent with near-maximal acute glucose lowering in preclinical studies. Across doses, no apparent adverse effects, including hypoglycemia, were found or reported. CONCLUSIONS: The results from this study in a select population of healthy male volunteers suggest that multiple oral doses of sitagliptin inhibited plasma DPP-IV activity and affected active GLP-1 concentrations in a dose-dependent manner, without producing hypoglycemia. Multiple dosing of sitagliptin exhibited a PK/PD profile consistent with that of a QD regimen and was well tolerated.

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.

BACKGROUND: 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. METHODS: Two double-blind, randomized, placebo-controlled, alternating-panel studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of sitagliptin (1.5-600 mg) in healthy male volunteers. RESULTS: Sitagliptin was well absorbed (approximately 80% excreted unchanged in the urine) with an apparent terminal half-life ranging from 8 to 14 hours. Renal clearance of sitagliptin averaged 388 mL/min and was largely uninfluenced by the dose administered. The area under the plasma concentration-time curve for sitagliptin increased in an approximately dose-dependent manner and was not meaningfully influenced by food. Single doses of sitagliptin markedly and dose-dependently inhibited plasma DPP-IV activity, with approximately 80% or greater inhibition of DPP-IV activity occurring at 50 mg or greater over a 12-hour period and at 100 mg or greater over a 24-hour period. Compared with placebo, sitagliptin produced an approximately 2-fold increase in postmeal active glucagon-like peptide 1 levels. Sitagliptin was well tolerated and was not associated with hypoglycemia. CONCLUSIONS: This study provides proof of pharmacologic characteristics for sitagliptin in humans. By inhibiting plasma DPP-IV activity, sitagliptin increases the postprandial rise in active glucagon-like peptide 1 concentrations without causing hypoglycemia in normoglycemic healthy male volunteers. Sitagliptin possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen.

A high-precision fluorogenic cholesteryl ester transfer protein assay compatible with animal serum and 3456-well assay technology.

Cholesteryl ester transfer protein (CETP) is a serum component responsible for both cholesteryl ester and triglyceride trafficking between high-density lipoprotein (HDL) and the apolipoprotein B (apoB)-containing very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). Several fluorescence-based assays that monitor these transfers have been reported, but to date such assays have suffered from a low signal/background (S/B) ratio and have been described for use only in relatively purified in vitro systems. We have modified the more advanced of these assays to incorporate a noninterfering, nondiffusable fluorescence quencher into previously described cosonicate particles, often referred to as microemulsions. This simple improvement resulted in particles that had an average threefold enhanced S/B window over particles without quenchers but that continued to show the essential properties of a catalytic assay, including catalysis to a single endpoint, excellent linearity with protein and particle concentration, and an appropriate sensitivity to inhibition. This reduced assay noise allowed the subsequent development of protocols for the direct measure of cholesteryl ester (CE) transfer activity resident in human and animal serum as well as the development of 384- and 3456-well screening protocols with good precision and accuracy. Thus, by expanding the dynamic response window of the assay, we have created an assay generalizable to many settings.