Idarucizumab does not have procoagulant effects: Assessment of thrombosis biomarkers in healthy volunteers.

Idarucizumab, a humanised monoclonal antibody fragment, binds dabigatran with high affinity and immediately, completely and sustainably reverses dabigatran-induced changes on blood coagulation. The present analysis focuses on the evaluation of potential procoagulant properties of idarucizumab when administered in the absence of dabigatran. As part of two Phase I studies conducted in healthy Caucasian and Japanese male volunteers, the effect of idarucizumab (8 g as a 1-hour [h] infusion and 4 g as a 5-minute [min] infusion) and placebo on calibrated automated thrombography (CAT) was assessed using platelet-poor plasma samples.

Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study.

Background And Objectives: Idarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy.

Methods: In this randomized, double-blind, crossover study, 46 subjects (12 middle-aged, 45-64 years; 16 elderly, 65-80 years; and 18 with mild or moderate renal impairment) received dabigatran etexilate (DE; 220 or 150 mg twice daily) for 4 days.

A phase I study of volasertib combined with afatinib, in advanced solid tumors.

Purpose: To determine the maximum tolerated dose (MTD) of volasertib, a Polo-like kinase inhibitor, combined with afatinib, an oral irreversible ErbB family blocker, in patients with advanced solid tumors (NCT01206816; Study 1230.20).

Methods: Patients with advanced non-resectable and/or metastatic disease following failure of conventional treatment received intravenous volasertib 150-300 mg on day 1 every 21 days, combined with oral afatinib 30-40 mg on days 2-21 of a 3-week cycle (Schedule A), or 50-90 mg on days 2-6 of a 3-week cycle (Schedule B).

Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir.

Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration = 31 nM in 50% human serum). The possible effects of ritonavir and efavirenz on raltegravir pharmacokinetics were separately examined. Two clinical studies of healthy subjects were conducted: for ritonavir plus raltegravir, period 1, 400 mg raltegravir; period 2, 100 mg ritonavir every 12 h for 16 days with 400 mg raltegravir on day 14; for efavirenz plus raltegravir, period 1, 400 mg raltegravir; period 2, 600 mg efavirenz once daily for 14 days with 400 mg raltegravir on day 12.

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.

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.

A dual PPAR alpha/gamma agonist increases adiponectin and improves plasma lipid profiles in healthy subjects.

Background: The objective of these studies was to evaluate the pharmacokinetics and pharmacodynamics of MK-0767, a prototypical dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma 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 1-80 mg 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.

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.

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.

Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients.

Background: Aprepitant is a selective neurokinin-1 receptor antagonist that is effective for the prevention of nausea and vomiting caused by highly emetogenic chemotherapy. In vitro, aprepitant is a moderate inhibitor of the CYP3A4 enzyme, which is involved in the clearance of several chemotherapeutic agents. In this study we examined the potential for aprepitant to affect the pharmacokinetics and toxicity of intravenously administered docetaxel, a chemotherapeutic agent that is primarily metabolized by CYP3A4.

Lack of effect of aprepitant on digoxin pharmacokinetics in healthy subjects.

Aprepitant is a highly selective neurokinin-1 receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine3 (5HT3) receptor antagonist, has been shown to be efficacious in the prevention of highly emetogenic chemotherapy-induced nausea and vomiting. In vitro data suggest that aprepitant is a substrate and a weak inhibitor of P-glycoprotein. Thus, the effect of aprepitant on the pharmacokinetics of digoxin, a P-glycoprotein substrate, was examined in a double-blind, placebo-controlled, randomized, two-period crossover study in 12 healthy subjects.

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

Background: Recent studies have suggested that antiemetic therapy with a triple combination of the neurokinin-1 receptor antagonist MK-869, a serotonin (5-HT(3)) 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.

Methods: This was a multicenter, double-blind, randomized, active agent-controlled study of 177 cisplatin-naïve patients with malignant disease.

Acute effect of L-796568, a novel beta 3-adrenergic receptor agonist, on energy expenditure in obese men.

Objective: Our objective was to investigate the thermogenic efficacy of single oral doses of the novel beta(3)-adrenergic receptor agonist L-796568 [(R )-N -[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]-phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]-benzenesulfonamide, dihydrochloride] in humans.

Methods: Twelve healthy overweight to obese men participated in this 2-center, 3-period, randomized, placebo-controlled, crossover trial. In each period subjects received 250 mg L-796568, 1000 mg L-796568, or placebo.