Effect of the Phosphate Binders Sevelamer Carbonate and Calcium Acetate on the Pharmacokinetics of Roxadustat After Concomitant or Time-separated Administration in Healthy Individuals.

Purpose: Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, treats anemia in chronic kidney disease. Hyperphosphatemia, a common complication in chronic kidney disease, is treated with phosphate binders (PBs). This study in healthy individuals investigated the effect of 2 PBs, sevelamer carbonate and calcium acetate, on the pharmacokinetic properties of a single oral dose of roxadustat administered concomitantly or with a time lag.

Multiple-dose clinical pharmacology of the selective orexin-1 receptor antagonist ACT-539313.

Aims: Compounds that selectively target orexin-1 receptors may be beneficial for the treatment of various disorders. The role of selective orexin-1 receptor antagonists (1-SORAs) in addictive behavior and stress/anxiety-related disturbances has been demonstrated in animals. ACT-539313, an orally active, potent 1-SORA, has been assessed in a clinical single-ascending dose study and exhibited good safety and tolerability.

First-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of SAR247799, a selective G-protein-biased sphingosine-1 phosphate receptor-1 agonist for endothelial protection.

Aims: SAR247799 is a selective G-protein-biased sphingosine-1 phosphate receptor-1 (S1P ) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first-in-class molecule differentiated from previous S1P -desensitizing molecules developed for multiple sclerosis, can activate S1P without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization).

A Three-Part, Randomised Study to Investigate the Safety, Tolerability, Pharmacokinetics and Mode of Action of BC 007, Neutraliser of Pathogenic Autoantibodies Against G-Protein Coupled Receptors in Healthy, Young and Elderly Subjects.

Background And Objective: BC 007 is a substance with a novel and innovative mode of action for the first-time causal treatment of chronic heart failure, associated with the occurrence of autoantibodies against the β1-adrenoceptor, and other diseases of mostly the heart and vascular system, being accompanied by the occurrence of functionally active agonistic autoantibodies against G-protein-coupled receptors (GPCR-AAb). The proposed mechanism of action of BC 007 is the neutralisation of these pathogenic autoantibodies which stimulate the respective receptor. To evaluate the safety, tolerability, pharmacokinetics and mode of action of BC 007, single intravenous infusions of increasing concentration were given to healthy young males and healthy elderly autoantibody-negative and autoantibody-positive participants of both sexes.

First-in-human study with ACT-539313, a novel selective orexin-1 receptor antagonist.

Aims: The orexin system is involved in anxiety behaviour and corresponding physiological reactions and constitutes a target for treatment of anxiety disorders. ACT-539313 is a potent, selective orexin-1 receptor antagonist being developed for the treatment of anxiety disorders. This first-in-human study investigated its single-dose pharmacokinetics (PK) including food effect, pharmacodynamics (PD), safety and tolerability.

Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes.

Background: Oral semaglutide is a novel tablet containing the human glucagon-like peptide-1 (GLP‑1) analogue semaglutide, co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The safety and pharmacokinetics of oral semaglutide were investigated in two randomised, double-blind, placebo-controlled trials.

Methods: In a single-dose, first-in-human trial, 135 healthy males received oral semaglutide (2-20 mg semaglutide co-formulated with 150-600 mg SNAC) or placebo with SNAC.

Multiple daytime administration of the selective orexin-2 receptor antagonist JNJ-42847922 induces somnolence in healthy subjects without residual central effects.

Background: Pharmacokinetics, pharmacodynamics and general safety and tolerability of JNJ-42847922, a selective orexin-2 receptor antagonist, were assessed in healthy subjects.

Methods: Five consecutive cohorts of healthy subjects were enrolled and received doses of 5-60 mg orally once daily over 10 days of JNJ-42847922 ( n=6) or placebo ( n=2). Concentrations of drug in plasma and urine were measured over 24 h after dosing on Days 1, 5 and 10.

Pharmacodynamic interaction between intravenous nitroglycerin and oral sacubitril/valsartan (LCZ696) in healthy subjects.

Purpose: Sacubitril/valsartan (LCZ696) and nitroglycerin share the second messenger cGMP and lower blood pressure. Given the potential for co-administration of both drugs in patients with heart failure, this study was designed to investigate the potential for a pharmacodynamic drug interaction affecting blood pressure.

Methods: In this double-blind, placebo-controlled, randomised, crossover study, 40 healthy subjects received sacubitril/valsartan 200 mg bid (97/103 mg bid) or placebo for 5 days.

No QTc Prolongation with Semaglutide: A Thorough QT Study in Healthy Subjects.

Introduction: Semaglutide is a glucagon-like peptide-1 (GLP-1) analog approved for the once-weekly treatment of type 2 diabetes. The objective of this 16-week, double-blind, single-center thorough QT study was to confirm that semaglutide treatment does not prolong cardiac repolarization versus placebo. Prolongation of the QT interval is a biomarker for ventricular tachyarrhythmia.

Effect of Multiple Doses of Omeprazole on the Pharmacokinetics, Safety, and Tolerability of Roxadustat in Healthy Subjects.

Background And Objectives: Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease. This study investigated the effect of multiple daily oral doses of omeprazole on the pharmacokinetics, safety, and tolerability of a single oral dose of roxadustat.

Methods: This phase 1, open-label, two-period, one-sequence, crossover study enrolled healthy subjects.

Effect of Semaglutide on the Pharmacokinetics of Metformin, Warfarin, Atorvastatin and Digoxin in Healthy Subjects.

Background And Objective: Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects.

Methods: Subjects received metformin (500 mg twice daily for 3.

The Hypoxia-inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat (FG-4592) and Warfarin in Healthy Volunteers: A Pharmacokinetic and Pharmacodynamic Drug-Drug Interaction Study.

Purpose: Roxadustat is a small-molecule hypoxia-inducible factor prolyl-hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in patients with chronic kidney disease (CKD). Warfarin is an oral anticoagulant with a narrow therapeutic window that is often prescribed to treat coexisting cardiovascular diseases in patients with CKD. This clinical trial was designed to evaluate the effect of roxadustat on warfarin pharmacokinetic and pharmacodynamic parameters.

Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects.

Background: Lixisenatide is a once-daily, prandial, short-acting glucagon-like peptide-1 receptor agonist. Its main antidiabetic effect is to delay gastric emptying to control postprandial plasma glucose excursions. The dose-response relationship of the integrated insulinotropic and gastrostatic response to lixisenatide in healthy volunteers after a standardized liquid meal was investigated.

Safety and pharmacokinetics of olokizumab, an anti-IL-6 monoclonal antibody, administered to healthy male volunteers: A randomized phase I study.

Interleukin-6 (IL-6) is implicated in the pathophysiology of several inflammatory conditions. Olokizumab, a humanized anti-IL-6 monoclonal antibody, selectively blocks the final assembly of the IL-6 signaling complex. A randomized, double-blind, placebo-controlled, phase I dose-escalation study assessed the safety and tolerability of escalating single doses of olokizumab administered intravenously (iv) or subcutaneously (sc) to 67 healthy male volunteers.

Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study.

Aims: Pasireotide, a multireceptor-targeted somatostatin analogue with efficacy in Cushing's disease and acromegaly, can affect glucose metabolism due to inhibition of insulin secretion and incretin hormone responses. A study was therefore conducted to evaluate different antihyperglycemic drugs in the management of pasireotide-associated hyperglycemia.

Methods: This was a 1-week, Phase I, open-label study.

A first-in-man study to evaluate the safety, tolerability, and pharmacokinetics of pasireotide (SOM230), a multireceptor-targeted somatostatin analog, in healthy volunteers.

Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for four of the five somatostatin receptor subtypes (sst(1,2,3) and sst(5)), and potential clinical activity in several neuroendocrine and oncologic conditions, including acromegaly, Cushing's disease, and neuroendocrine tumors (NET). This manuscript reports the first-in-man dose-escalation study of pasireotide, evaluating its safety, tolerability, and pharmacokinetics (PK) in healthy male volunteers. A single dose of pasireotide 1-1200 μg was administered subcutaneously in four to eight subjects per dose level, with two additional subjects per cohort administered placebo.

Effects of yogurt and applesauce on the oral bioavailability of nilotinib in healthy volunteers.

Nilotinib, a potent orally bioavailable BCR-ABL tyrosine kinase inhibitor, is currently available as a hard gelatin capsule that must be swallowed whole. For patients who may have difficulty swallowing the intact capsule, an alternative mode of administration is desirable. The authors compared the bioavailability of nilotinib from the following administrations in 48 healthy subjects: (1) 400 mg nilotinib given as two 200-mg nilotinib intact capsules; (2) contents of two 200-mg nilotinib capsules, each capsule dispersed in 1 teaspoon of nonfat plain yogurt; and (3) contents of two 200-mg nilotinib capsules, each capsule dispersed in 1 teaspoon of applesauce.

Effects of nilotinib on single-dose warfarin pharmacokinetics and pharmacodynamics: a randomized, single-blind, two-period crossover study in healthy subjects.

Background And Objective: Nilotinib (Tasigna®), a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukaemia in the chronic phase (CML-CP) and the accelerated phase (CML-AP) in patients resistant or intolerant to prior therapy, including imatinib. Nilotinib has shown competitive inhibition of cytochrome P450 enzyme (CYP) 2C9 in vitro, but its effect on CYP2C9 activity in humans is unknown. This study evaluated the effects of nilotinib on the pharmacokinetics and pharmacodynamics of warfarin, a sensitive CYP2C9 substrate, in healthy subjects.

Effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of nilotinib.

Nilotinib (Tasigna), a highly selective and potent BCR-ABL tyrosine kinase inhibitor (TKI), is administered orally and has pH-dependent aqueous solubility, with lower dissolution at higher pH. This study evaluated the effect of esomeprazole on the pharmacokinetics of nilotinib in healthy participants. Twenty-two participants (6 women, 16 men, mean age of 44.

The prokinetic cinitapride has no clinically relevant pharmacokinetic interaction and effect on QT during coadministration with ketoconazole.

The present clinical trial was designed to evaluate the possible pharmacokinetic and electrocardiographic interactions of the gastroenteric prokinetic drug cinitapride with ketoconazole. The safety and tolerability of the study treatments were also evaluated. After a placebo-controlled, double-blind, crossover design, 16 healthy male (n = 8) and female (n = 8) volunteers were randomized into four treatment groups of four subjects (two males and two females): cinitapride (CTP; 1 mg t.

Safety of hydroxocobalamin in healthy volunteers in a randomized, placebo-controlled study.

Introduction: This randomized, double-blind, placebo-controlled, ascending-dose study was conducted in healthy volunteers to evaluate the safety of the investigational cyanide antidote hydroxocobalamin.

Methods: Four ascending dosing groups received intravenous doses of 2.5, 5, 7.

An open-label, parallel group study investigating the effects of age and gender on the pharmacokinetics of the once-daily glucagon-like peptide-1 analogue liraglutide.

Liraglutide is a once-daily glucagon-like peptide-1 analogue being developed for the treatment of type 2 diabetes. The aim of this study was to investigate the effect of age and gender on the pharmacokinetics of liraglutide. Eight male and 8 female subjects were recruited from an 18- to 45-year-old group and an over-65-year-old group, respectively.

Clinical pharmacokinetics of alamifovir and its metabolites.

Alamifovir, a purine nucleotide analogue prodrug, and its hydrolyzed derivatives have shown preclinical efficacy activity against wild-type and lamivudine-resistant hepatitis B virus. Two studies were conducted to examine the single- and multiple-dose alamifovir pharmacokinetics after oral administration in healthy males. In study 1, subjects were given single doses (0.

Tissue concentrations and induction of a hepatic monooxygenase in male Wistar rats after repeated doses of defined polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDDs and PCDFs) mixtures.

Two groups of male Wistar rats were treated 16 times (every 3rd day) subcutaneously with a defined mixture of polychlorinated dibenzo-p-dioxins (PCDDs) or of polychlorinated dibenzofurans (PCDFs). These mixtures contained no measurable amount of 2,3,7,8-TCDD. Each single dose was calculated to contain either 57 ng I-TEq (international 2,3,7,8-T4CDD toxicity equivalencies)/kg body weight of the PCDD mixture or 39 ng I-TEq/kg body weight of the PCDF mixture.

Effect of food on everolimus absorption: quantification in healthy subjects and a confirmatory screening in patients with renal transplants.

Study Objective: To quantify the influence of a high-fat meal on the oral bioavailability of the immunosuppressant everolimus in a single-dose study in healthy subjects and to confirm the results in a small food-effect screening assessment in patients with renal transplants who were receiving multiple-dose everolimus.

Design: Randomized, open-label, crossover, single-dose study and confirmatory screening.

Setting: Phase 1 unit for the single-dose study and two German hospitals for the patient screening.