Effects of sugammadex on activated partial thromboplastin time and prothrombin time in healthy subjects.

OBJECTIVES: To assess the impact of sugammadex on activated partial thromboplastin time (APTT) and international normalized ratio for prothrombin time (PT(INR)) in healthy subjects and characterize the concentration-dependency of sugammadex effects on APTT and prothrombin time (PT) in normal human plasma in vitro. METHODS: Eight healthy subjects (18 - 45 years of age) were administered intravenous doses of 4 mg/kg sugammadex, 16 mg/kg sugammadex, or placebo in a randomized, placebo-controlled, three period cross-over trial. The primary endpoint was area under the curve from 2 to 60 minutes post-dose (AUC2-60min) for APTT and PT(INR). In vitro, the effects of sugammadex on APTT and PT were assessed in pooled normal human citrate plasma. RESULTS: In subjects dosed with 4 and 16 mg/kg sugammadex, geometric mean ratios (treated vs. placebo) for AUC2-60min were 1.085 (95% confidence interval, 0.888 - 1.325) and 1.019 (0.868 - 1.195), respectively, for APTT, and 1.047 (0.904 - 1.213) and 1.096 (0.953 - 1.261), respectively, for PT(INR). At individual timepoints, mean APTT and PT(INR) increased by up to 22% after 16 mg/kg sugammadex compared with placebo. All such increases occurred within 30 minutes post-dose. Sugammadex was generally well tolerated. In the in vitro experiments, addition of sugammadex to plasma resulted in limited, concentration dependent increases in both APTT and PT. At 200 µg/mL (the mean maximum concentration reached therapeutically), the relative increases were 29% and 19%, respectively. CONCLUSIONS: Administration of sugammadex is associated with a dose-related, limited and transient prolongation of APTT and PT(INR) that is unlikely to be of clinical relevance.

Lack of a clinically relevant effect of sugammadex on anti-Xa activity or activated partial thromboplastin time following pretreatment with either unfractionated or low-molecular-weight heparin in healthy subjects.

OBJECTIVE: To investigate the potential effect of sugammadex on anti-Xa anticoagulantactivity of enoxaparin and the activated partial thromboplastin time (APTT) of unfractionated heparin (UFH). METHODS: This two-part, randomized, double-blind, placebocontrolled, four-period cross-over study was performed in healthy males (18 - 45 years). In each period, subjects received 40 mg enoxaparin (in part 1), 5,000 units UFH (in part 2), or placebo followed by 4 or 16 mg/kg sugammadex, or placebo. Treatments were separated by ≥ 4 days. Primary endpoints were anti-Xa activity and APTT both time-averaged from 3 to 30 minutes post-dose. Geometric mean ratios (GMRs) and their two-sided 90% confidence limits were calculated for anticoagulant plus sugammadex (4 or 16 mg/kg) vs. anticoagulant plus placebo. The pre-specified threshold for a potential effect of clinical relevance was a 90% upper confidence limit (UCL) > 1.50. RESULTS: In part 1 (n = 13), the 90% UCLs were 1.07 and 1.08 for GMRs of anti-Xa activity after dosing with 4 and 16 mg/kg sugammadex, respectively. In part 2 (n = 43), the 90% UCLs for GMRs of APTT were 1.06 and 1.15. Neither sugammadex dose produced a treatment effect that met the pre-specified criterion for potential clinical relevance. Treatments were generally well tolerated. CONCLUSIONS: In healthy subjects, treatment with 4 mg/kg and 16 mg/kg sugammadex did not change either anti-Xa activity or APTT to a clinically meaningful extent following pretreatments with enoxaparin or UFH.

Pharmacokinetic-pharmacodynamic studies of the 11ß-hydroxysteroid dehydrogenase type 1 inhibitor MK-0916 in healthy subjects.

AIMS: To characterize pharmacokinetic parameters of MK-0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable-isotope labelling) the in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916. METHODS: Data are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first study, subjects received single oral doses of 0.4-100 mg MK-0916 (n = 16). In the second study, subjects received 0.2-225 mg MK-0916 followed by daily doses of 0.2-100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [(13)C4]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [(13)C4]cortisone. RESULTS: Doses ≥3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1-1.8 h). Exposure (measured as the area under the concentration-time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nm and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11ß-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nm. Exposure to MK-0916 was generally well tolerated. CONCLUSIONS: These findings indicate that 11ß-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated.

Pharmacokinetics of the novel PAR-1 antagonist vorapaxar in patients with hepatic impairment.

PURPOSE: To determine whether hepatic impairment has an effect on the pharmacokinetics (PK) of vorapaxar or M20, its main pharmacologically active metabolite. METHODS: This was an open-label study in which a single 40-mg oral dose of vorapaxar was administered to patients with mild (n = 6), moderate (n = 6), and severe (n = 4) hepatic impairment and healthy controls (n = 16) matched for age, gender, weight, and height. Blood samples for vorapaxar and M20 assay were collected predose and at frequent intervals up to 8 weeks postdose. RESULTS: Plasma vorapaxar and M20 PK profiles were similar between patients with impaired liver function and healthy controls. Group mean values for vorapaxar C(max) and AUC(tf) were 206-279 ng/mL and 14,200-18,200 ng·h/mL, respectively, with the lowest values observed in patients with severe impairment. Vorapaxar median T(max) and mean t(1/2) values were 1.00-1.75 h and 298-366 h, respectively. There was no apparent correlation between vorapaxar or M20 exposure or t(1/2) values and disease severity. Vorapaxar was generally well tolerated; one serious adverse event (gastrointestinal bleeding secondary to ruptured esophageal varices) was reported in a patient with severe hepatic impairment. CONCLUSIONS: Hepatic impairment had no clinically relevant effect on the PK of vorapaxar and M20. No dose or dosage adjustment of vorapaxar will be required in patients with mild to moderate hepatic impairment. Although systemic exposure to vorapaxar does not appear to increase in patients with severe hepatic impairment, administration of vorapaxar to such patients is not recommended given their bleeding diathesis.

Pharmacokinetics and pharmacodynamics of the novel PAR-1 antagonist vorapaxar in patients with end-stage renal disease.

PURPOSE: To determine whether impaired renal function alters the pharmacokinetics (PK) of vorapaxar or its ability to inhibit thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. METHODS: This was an open-label study in which 8 patients with end-stage renal disease (ESRD) on hemodialysis and 7 matched (based on age, gender, weight, and height) healthy controls were administered a single 10-mg oral dose of vorapaxar. Blood samples for vorapaxar PK and pharmacodynamic analysis were collected predose and at frequent intervals up to 6 weeks postdose. RESULTS: Mean vorapaxar bioavailability (based on area under the curve of plasma vorapaxar concentration over time) was identical in the two subject groups; the ESRD/healthy geometric mean ratio (GMR, expressed in percent) was 98. Mean maximum observed plasma concentration (77.4-98.2 ng/mL) was numerically lower in patients with ESRD compared with matched controls (GMR=76; 90% confidence interval=48 to 118). Median time of maximum observed plasma concentration was 2 h in both subject groups. The observed means for elimination half-life were 186 and 231 h in the ESRD and control groups, respectively. Inhibition of platelet aggregation was similar in the two groups. Four out of 15 (27%) subjects reported adverse events, all of which were characterized by the investigator as mild and unrelated to treatment. CONCLUSIONS: ESRD had no clinically relevant effect on the PK profile of vorapaxar or its ability to inhibit TRAP-induced platelet aggregation.

Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs.

Glucokinase activators (GKAs) are small-molecule agents that enhance glucose sensing by pancreatic ß cells and glucose metabolism by hepatocytes. There is strong interest in these agents as potential therapies for type 2 diabetes. Here, we report key pharmacokinetic and pharmacodynamic findings from preclinical studies of the GKA 3-[[6-(ethylsulfonyl)-3-pyridinyl]oxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (MK-0941). Incubated in vitro with recombinant human glucokinase, 1 µM MK-0941 lowered the S(0.5) of this enzyme for glucose from 6.9 to 1.4 mM and increased the maximum velocity of glucose phosphorylation by 1.5-fold. In 2.5 and 10 mM glucose, the EC(50) values for activation of GK by MK-0941 were 0.240 and 0.065 µM, respectively. Treatment of isolated rat islets of Langerhans and hepatocytes with 10 µM MK-0941 increased insulin secretion by 17-fold and glucose uptake up to 18-fold, respectively. MK-0941 exhibited strong glucose-lowering activity in C57BL/6J mice maintained on a high-fat diet (HFD), db/db mice, HFD plus low-dose streptozotocin-treated mice, and nondiabetic dogs. In both mice and dogs, oral doses of MK-0941 were rapidly absorbed and rapidly cleared from the blood; plasma levels reached maximum within 1 h and fell thereafter with a half-life of ~2 h. During oral glucose tolerance testing in dogs, MK-0941 reduced total area-under-the-curve postchallenge (0-2 h) plasma glucose levels by up to 48% compared with vehicle-treated controls. When administered twice daily to mice for 16 days, and once daily to the dog for 4 days, MK-0941 remained efficacious on successive days. These findings support further investigation of MK-0941 as a potential therapeutic agent for treatment of type 2 diabetes.

Evaluation of pharmacokinetic parameters and dipeptidyl peptidase-4 inhibition following single doses of sitagliptin in healthy, young Japanese males.

AIMS: Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males. METHODS: In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20-46 years) in each panel received single oral doses of 5-400mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0-48h post dose and plasma DPP-4 inhibition from 0-24h post dose. The results were compared with historical data from young, healthy non-Japanese males. RESULTS: Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2-6h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9-14h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73-1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin ≥50mg resulted in weighted average DPP-4 inhibition from 0-24h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia. CONCLUSIONS: The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes.

A systematic review of in-hospital worsening heart failure as an endpoint in clinical investigations of therapy for acute heart failure.

BACKGROUND: In-hospital worsening heart failure (WHF) occurs frequently in patients hospitalized for acute heart failure (AHF) and has strongly negative prognostic associations. It may be a useful endpoint in studies of AHF management but important questions remain regarding optimization of its definition and variability in its incidence. METHODS: Our objective was to survey the full extent of clinical interest in WHF and assess the impact of baseline variables and trial design on outcomes. PubMed, Embase, and BIOSIS were searched systematically for clinical studies that had in-hospital WHF as an endpoint. Differences in definitions of in-hospital WHF were reviewed for their potential impact on observed incidence of WHF and its associations with post-discharge outcomes. RESULTS: The search identified 35 publications representing 13 interventional trials, 3 observational studies, several different classes of therapeutic agent, and 78,752 patients overall. Incidence of in-hospital WHF varied greatly-from 4.2% to 37%. Concerning the impact of differences in the way in which WHF was defined, two important factors were physician determination of worsening and whether intensification of diuretic therapy alone was defined as a WHF event. Patients having in-hospital WHF were at substantially greater risk for death and longer length of stay during index hospitalizations, all-cause and heart-failure rehospitalization, cardiovascular complications, renal failure, all-cause death, cardiovascular death, and higher healthcare costs post-discharge. CONCLUSIONS: There is diverse interest in selecting in-hospital WHF as an endpoint in clinical trials. Differences in reported incidence are complexly related to differences in the way in which WHF is defined.

Montelukast in the treatment of allergic rhinitis: an evidence-based review.

Cysteinyl-leukotrienes (CysLTs) are endogenous mediators of inflammation and play an important role in allergic airway disease by stimulating bronchoconstriction, mucus production, mucosal oedema and inflammation, airway infiltration by eosinophils, and dendritic cell maturation that prepares for future allergic response. Montelukast inhibits these actions by blocking type 1 CysLT receptors found on immunocytes, smooth muscle and endothelium in the respiratory mucosa. Initially developed as a treatment for asthma, montelukast has more recently found use in the treatment of allergic rhinitis (AR). We conducted a systematic review of studies that have evaluated montelukast in the treatment of seasonal AR (SAR) and perennial AR (PAR), with and without concomitant asthma. Primary consideration was given to large, randomised, placebo-controlled, double-blind clinical trials in which AR endpoints were assessed and the use of concurrent treatments for AR was excluded. Eight such studies were found in the literature. The primary endpoint in these was daytime nasal symptom severity represented by a composite score derived from individual self-ratings of nasal congestion, rhinorrhoea, nasal pruritus and sneezing. Secondary endpoints have included these individual nasal symptom scores, additional scores for eye, ear and throat symptoms, the impact of rhinitis on quality of sleep, global evaluations of outcome by patients and physicians, and measures of the severity of concomitant asthma. A general outcome was that patients treated with montelukast had significantly greater improvements in their symptoms of SAR and PAR than did patients who were given a placebo. As monotherapy, montelukast exhibited efficacy similar to that of loratadine, but less than that of the intranasally administered corticosteroid fluticasone propionate. The use of montelukast in combination with antihistamines such as loratadine or cetirizine has generally resulted in greater efficacy than when these agents were used alone, and in some studies has produced results comparable with intranasally applied corticosteroids. In patients with AR comorbid with asthma, montelukast treatment has resulted in significant improvements in both, compared with placebo. Montelukast is well tolerated and has a favourable safety profile; adverse events have occurred at similar frequencies in patients taking either montelukast or placebo. Montelukast provides an effective and well tolerated oral treatment for allergic airway inflammation in patients with SAR or PAR without asthma, and in patients in whom AR is comorbid with asthma.

Single-dose montelukast or salmeterol as protection against exercise-induced bronchoconstriction.

BACKGROUND AND OBJECTIVE: It has been previously established that montelukast provides protection against exercise-induced bronchoconstriction (EIB) after a single dose. The present objective was to assess the onset and duration of this protective action in a trial that included both positive and negative controls. METHODS: A randomized, active-controlled and placebo-controlled, double-blind, double-dummy, three-way crossover study was conducted in 47 patients (age range, 15 to 44 years) in whom there was a 20 to 40% fall in FEV(1) following exercise (DeltaFEV(1)). In randomized sequence, patients received oral montelukast (10 mg), placebo, or inhaled salmeterol (50 microg) as a positive control. Dosing was followed by exercise challenges at 2, 8.5, and 24 h. The primary end point was maximum DeltaFEV(1) at 2 h postdose. Secondary end points included maximum DeltaFEV(1) at the two later time points, and other measures (including recovery time and need for beta-agonist rescue) at all time points. RESULTS: The maximum DeltaFEV(1) magnitudes at 2, 8.5, and 24 h were significantly smaller after montelukast administration than after placebo administration (least squares mean [+/- SE], 13.2 +/- 1.2%, 11.7 +/- 1.2%, and 10.0 +/- 1.1% vs 21.8 +/- 1.2%, 16.8 +/- 1.3%, and 14.0 +/- 1.1%, respectively; p

A randomized, phase II study of the anti-insulin-like growth factor receptor type 1 (IGF-1R) monoclonal antibody robatumumab (SCH 717454) in patients with advanced colorectal cancer.

Overexpression of insulin-like growth factor receptor type 1 (IGF-1R) may promote tumor development and progression in some cancer patients. Our objective was to assess tumor uptake of fluorodeoxyglucose by positron-emission tomography in patients with chemotherapy-refractory colorectal cancer treated with an anti-insulin-like growth factor receptor type 1 (anti-IGF-1R) monoclonal antibody, robatumumab. This was a randomized, open-label study with two periods (P1 and P2). Patients were randomized 3:1 into treatment arms R/R and C/R that received, respectively, one cycle of 0.3 mg/kg robatumumab or one or more cycles of second-line chemotherapy in P1, followed in either case by 10 mg/kg robatumumab biweekly in P2. The primary measure of fluorodeoxyglucose uptake was maximum standardized uptake value (SUV(max)). The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUV(max) (DiSUV) greater than 20% 12-14 days postdose in P2. Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)-defined tumor response and pharmacodynamic measures of target engagement. Among 41 patients who were evaluable for the primary endpoint, seven (17%, 95% CI 7%-32%) had DiSUV greater than 20%. Fifty robatumumab-treated patients were evaluable for RECIST-defined tumor response and six (12%) had stable disease lasting greater than or equal to 7 weeks in P2. Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab, but not 0.3 mg/kg. The most frequently reported adverse events were fatigue/asthenia, nausea, anorexia, and gastrointestinal disturbances. In this study, few patients with chemotherapy-refractory colorectal cancer appeared to benefit from treatment with the IGF-1R antagonist robatumumab.

Humoral immunity and delayed-type hypersensitivity in healthy subjects treated for 30 days with MK-7123, a selective CXCR2 antagonist.

Antagonism of the chemokine receptor CXCR2 inhibits neutrophil trafficking and may thus be therapeutic in patients with chronic obstructive pulmonary disease and other lung disorders in which there is substantial infiltration by neutrophils. Here, we report the findings from a randomized, placebo-controlled, double-blind clinical trial of the small-molecule CXCR2 antagonist MK-7123 (formerly SCH 527123) that evaluated potential downstream effects of CXCR2 antagonism on immunogenic competency (B cell antibody response) in the adaptive immune system and delayed-type hypersensitivity (DTH) in healthy subjects (ages 34-65 years) dosed once daily for 30 days either with 30 mg MK-7123 (n=24) or placebo (n=7). Eligible subjects were seronegative for anti-hepatitis A virus (HAV) immunoglobulin G (IgG) and positive for DTH response to intradermal injection of Candida albicans antigen at screening. Subjects were vaccinated for HAV on treatment Day 2. The primary endpoints were anti-HAV IgG titer on Day 30 and DTH response magnitude on Day 27. Pharmacokinetic and safety endpoints were also assessed. We observed that anti-HAV IgG titers and DTH responses did not differ significantly between MK-7123-treated and placebo-treated subjects. Twenty-eight days postvaccination, seroconversion (anti-HAV IgG titer≥10mIU/mL) was observed in 87.5% and 85.7% of MK-7123-treated and placebo-treated subjects, respectively; mean (±SE) titers were 27.3±5.5 and 21.4±4.3mIU/mL, respectively. Treatment with MK-7123 was generally well tolerated. Doses were followed by temporary reductions in absolute peripheral blood neutrophil count. In conclusion, this study found that B cell response and cell-mediated immunity were not altered by CXCR2 antagonism with MK-7123.

Dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes treated with saxagliptin, sitagliptin, or vildagliptin.

INTRODUCTION: Saxagliptin, sitagliptin, and vildagliptin are dipeptidyl peptidase-4 (DPP-4) inhibitors widely approved for use in patients with type 2 diabetes. Using a crossover design, the present study compared trough levels of DPP-4 inhibition provided by these agents in a single cohort of patients with type 2 diabetes. METHODS: This was a randomized, placebo-controlled, open-label, five-period crossover study. Eligible patients were 18-65 years of age, either treatment-naïve or off prior antihyperglycemic agent therapy for at least 6 or 12 weeks (depending on the prior therapy), and had glycated hemoglobin (HbA1C) ≥6.5% and ≤10.0%. In separate study periods, patients received 5 mg saxagliptin q.d. (saxa-5), 100 mg sitagliptin q.d. (sita-100), 50 mg vildagliptin q.d. (vilda-50-q.d.), 50 mg vildagliptin b.i.d. (vilda-50-b.i.d.), or placebo for 5 days. The primary endpoint was trough %DPP-4 inhibition, derived by comparing DPP-4 activity 24 h after the Day-5 morning dose with predose activity in the same period and analyzed using a linear mixed-effects model with fixed-effects terms for treatment and period. RESULTS: Mean (range) baseline HbA1C was 7.4% (6.4-9.0%; N = 22). Least-squares (LS) mean trough %DPP-4 inhibition was 73.5%, 91.7%, 28.9%, 90.6%, and 3.5% after saxa-5, sita-100, vilda-50-q.d., vilda-50-b.i.d., and placebo, respectively. In patients treated with sita-100, the LS-mean difference in trough %DPP-4 inhibition was 18.2% greater than with saxa-5 (p < 0.001), 62.9% greater than with vilda-50-q.d. (p < 0.001), 1.1% greater than with vilda-50-b.i.d. (p = 0.128), and 87.8% greater than with placebo (p < 0.001). Mean %DPP-4 inhibition was nearly maximal at 12 h postdose regardless of active treatment. Thus, these between-group comparisons at trough primarily reflected differences in duration of action. Adverse events reported during the study were transient and mild or moderate in intensity. CONCLUSION: Once daily treatment with sitagliptin provided trough DPP-4 inhibition significantly greater than saxagliptin or vildagliptin administered once daily, and similar to that provided by vildagliptin administered twice daily.

Efficacy and safety of sitagliptin added to ongoing metformin and rosiglitazone combination therapy in a randomized placebo-controlled 54-week trial in patients with type 2 diabetes.

BACKGROUND: New therapeutic approaches are needed to improve glycemic control in patients with type 2 diabetes (T2D), a progressive disorder that often requires combination therapy. The present study assessed the efficacy and safety of sitagliptin as add-on therapy to metformin and rosiglitazone in patients with T2D. METHODS: The present study was a randomized double-blind placebo-controlled parallel-group 54-week study conducted at 41 sites across North and South America, Europe, and Asia in 278 patients with HbA1c ranging from ≥7.5% to ≤11.0% despite ongoing combination therapy with metformin (≥1500 mg/day) and rosiglitazone (≥4 mg/day). Patients were randomized (2:1) to receive sitagliptin 100 mg or placebo once daily. The main outcome measure was change from baseline in HbA1c at Week 18. RESULTS: Mean baseline HbA1c was 8.8%. The mean placebo-adjusted change from baseline in HbA1c with sitagliptin treatment was -0.7% (P < 0.001) at Week 18 and -0.8% (P < 0.001) at Week 54. There were also significant (P < 0.001) reductions in 2-h post-meal glucose and fasting plasma glucose compared with placebo at Weeks 18 and 54. Significantly higher proportions of sitagliptin- than placebo-treated patients had HbA1c<7.0% at Weeks 18 (22% vs 9%; P = 0.003) and 54 (26% vs 14%; P = 0.015). Changes in body weight and the rates of adverse events overall, hypoglycemia, and gastrointestinal adverse events were similar in the sitagliptin and placebo groups during the 54-week study. CONCLUSIONS: In patients with T2D, the addition of sitagliptin for 54 weeks to ongoing therapy with metformin and rosiglitazone improved glycemic control and was generally well tolerated compared with placebo.

Anti-diabetic efficacy and impact on amino acid metabolism of GRA1, a novel small-molecule glucagon receptor antagonist.

Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR) and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism.

Efficacy and safety of the selective 11ß-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension.

11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) may be involved in several abnormalities associated with the metabolic syndrome. This study evaluated the antihypertensive efficacy and safety of two 11ß-HSD1 inhibitors, MK-0736 and MK-0916, in overweight-to-obese hypertensive patients. Patients aged 18-75 years with sitting diastolic blood pressure (SiDBP) 90-104 mm Hg, systolic BP <160 mm Hg (after washout of prior antihypertensive medications), and BMI ≥27 to <41 kg/m(2) were randomized to receive 2 or 7 mg/d MK-0736, 6 mg/d MK-0916, or placebo for 12 weeks (n = 51-54/group). Patients with BMI ≥20 to <27 kg/m(2) received 6 mg/d MK-0916 or placebo for 24 weeks (n = 19/group). The primary endpoint was placebo-adjusted change from baseline in trough SiDBP in patients treated for 12 weeks with 7 mg/d MK-0736. The primary endpoint was not met (placebo-adjusted reduction = 2.2 mm Hg; P = .157). With 7 mg/d MK-0736, placebo-adjusted LDL-C decreased by 12.3%, high-density lipoprotein cholesterol by 6.3%, and body weight by 1.4 kg. Both 11ß-HSD1 inhibitors were generally well tolerated. In overweight-to-obese patients with hypertension, reduction in SiDBP with MK-0736 was not statistically significant. Nonetheless, MK-0736 was well tolerated and did appear to modestly improve other BP endpoints, LDL-C, and body weight.

Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Type 2 diabetes in the elderly is an important and insufficiently studied public health problem. This study evaluated sitagliptin monotherapy in patients with type 2 diabetes aged ≥ 65 years. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group study conducted at 52 sites in the United States. Patients were treated with once-daily sitagliptin (100 or 50 mg, depending on renal function) or placebo for 24 weeks. Key endpoints included change from baseline in glycated hemoglobin (HbA(1c)), 2-hour post-meal glucose (2-h PMG) and fasting plasma glucose (FPG) at week 24, and average blood glucose on treatment days 3 and 7. CLINICAL TRIAL REGISTRATION: NCT00305604. RESULTS: Among randomized patients (N = 206), mean age was 72 years and mean baseline HbA(1c) was 7.8%. At week 24, HbA(1c) decreased by 0.7%, 2-h PMG by 61 mg/dL, and FPG by 27 mg/dL in sitagliptin-treated patients compared with placebo (all p < 0.001). On day 3 of treatment, mean average blood glucose was decreased from baseline by 20.4 mg/dL in sitagliptin-treated patients compared with placebo (p < 0.001). In subgroups defined by baseline HbA(1c) <8.0% (n = 132), ≥ 8.0% to <9.0% (n = 42), and ≥ 9.0% (n = 18), the placebo-adjusted reductions in HbA(1c) with sitagliptin treatment were 0.5%, 0.9%, and 1.6%, respectively. Patients in the sitagliptin and placebo groups had similar rates of adverse events overall (46.1% and 52.9%, respectively); serious adverse events were reported in 6.9% and 13.5%, respectively. No adverse events of hypoglycemia were reported. Potential study limitations include a relatively small number of patients with more severe hyperglycemia (HbA(1c) ≥ 9.0%) and the exclusion of patients with severe renal insufficiency. CONCLUSION: In this study, sitagliptin treatment significantly and rapidly improved glycemic measures and was well tolerated in patients aged ≥ 65 years with type 2 diabetes.

Effects of peripherally administered neuromedin U on energy and glucose homeostasis.

Neuromedin U (NMU) is a highly conserved peptide reported to modulate energy homeostasis. Pharmacological studies have shown that centrally administered NMU inhibits food intake, reduces body weight, and increases energy expenditure. NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU become lean and hypophagic. Two high-affinity NMU receptors, NMUR1 and NMUR2, have been identified. NMUR1 is found primarily in the periphery and NMUR2 primarily in the brain, where it mediates the anorectic effects of centrally administered NMU. Given the broad expression pattern of NMU, we evaluated whether peripheral administration of NMU has effects on energy homeostasis. We observed that acute and chronic peripheral administration of NMU in rodents dose-dependently reduced food intake and body weight and that these effects required NMUR1. The anorectic effects of NMU appeared to be partly mediated by vagal afferents. NMU treatment also increased core body temperature and metabolic rate in mice, suggesting that peripheral NMU modulates energy expenditure. Additionally, peripheral administration of NMU significantly improved glucose excursion. Collectively, these data suggest that NMU functions as a peripheral regulator of energy and glucose homeostasis and the development of NMUR1 agonists may be an effective treatment for diabetes and obesity.

A phase I pharmacokinetic and pharmacodynamic study of dalotuzumab (MK-0646), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in patients with advanced solid tumors.

PURPOSE: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose. EXPERIMENTAL DESIGN: Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses. RESULTS: Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean C(min) was more than 25 µg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. (18)F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewing's sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively. CONCLUSIONS: Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals.