Pharmacokinetics, Safety, and Tolerability of Vonoprazan- or Esomeprazole-Based Bismuth-Containing Quadruple Therapy: A Phase 1, Double-Blind, Parallel-Group Study in Adults with Helicobacter pylori Infection in China.

Quadruple therapy comprising 2 antibiotics, a proton pump inhibitor, and bismuth, is recommended for Helicobacter pylori eradication in China. This Phase 1, double-blind, parallel-group study aimed to evaluate the pharmacokinetics, safety, and tolerability of bismuth-containing vonoprazan- or esomeprazole-based quadruple therapy in H. pylori-positive healthy subjects at a single site in China.

Randomized clinical trial: A double-blind, proof-of-concept, phase 2 study evaluating the efficacy and safety of vonoprazan 20 or 40 mg versus esomeprazole 40 mg in patients with symptomatic gastro-esophageal reflux disease and partial response to a healing dose of a proton-pump inhibitor.

Background: Proton-pump inhibitors (PPIs) are cornerstone treatments for gastro-esophageal reflux disease (GERD); however, evidence suggests that most patients exhibit partial response to PPIs, suggesting the need for novel therapies that can provide an improved and sustained increase in gastric pH.

Aims: This study aimed to determine the effect of vonoprazan, a novel, orally active small-molecule potassium-competitive acid blocker, versus esomeprazole, a PPI, in preventing heartburn symptoms over a 4-week treatment period in patients with GERD and a partial response to esomeprazole treatment.

Methods: This randomized, double-blind, proof-of-concept, phase 2 clinical trial was conducted between 2016 and 2018 at 39 sites across Europe and designed to evaluate the efficacy and safety of vonoprazan 20 mg once daily (q.

The Effect of Hepatic Impairment on the Pharmacokinetics of Intravenously Administered Felcisetrag (TAK-954).

Felcisetrag (formerly known as TAK-954) is a selective serotonin receptor agonist under investigation for use in patients with postoperative gastrointestinal dysfunction. The safety, tolerability, and pharmacokinetics (PK) of intravenous (i.v.

Clinical and Nonclinical Disposition and In Vitro Drug-Drug Interaction Potential of Felcisetrag, a Highly Selective and Potent 5-HT Receptor Agonist.

Background And Objective: Felcisetrag (previously TAK-954 or TD-8954) is a highly selective and potent 5-HT receptor agonist in clinical development for prophylaxis and treatment of postoperative gastrointestinal dysfunction (POGD). The rat, dog, and human absorption, distribution, metabolism, and excretion (ADME) properties of felcisetrag were investigated.

Methods: The metabolism and victim and perpetrator drug interaction potentials towards cytochrome P450s (CYP) and transporters were determined using in vitro models.

Characterizing Effects of Antidiabetic Drugs on Heart Rate, Systolic and Diastolic Blood Pressure.

A model-based meta-analysis was performed with reported data from obese subjects and patients with type 2 diabetes (T2DM) to characterize the effects of dipeptidyl peptidase 4 (DPP4) inhibitors, gastric inhibitory polypeptides (GIPs), glucagon-like peptide-1 (GLP1), and dual GIP/GLP1 agonists, or a combination of these antidiabetic drugs (ADs) on heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP). A systematic literature search and review after the Cochrane method identified sources for investigational and approved ADs resulted in a comprehensive database with data from 178 clinical studies in obese subjects and patients with T2DM. Results indicated that there were AD class-dependent effects on HR and SBP, whereas no clear AD-related effects on DBP were found.

Collaborations between Clinical Pharmacologists in Japan and in the United States - Report from the IQ CPLG and JPMA CPTF Meeting in Tokyo, Japan.

The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Clinical Pharmacology Leadership Group (CPLG) held its first meeting of Japan-based representatives at Astellas Pharma headquarters in Tokyo on October 1, 2019. The meeting was also attended by Japan Pharmaceutical Manufactures Association (JPMA) Clinical Pharmacology Task Force (CPTF) members. Overall, nearly 30 clinical pharmacologists representing 14 companies attended the event.

In Vitro Assessment of Potential for CYP-Inhibition-Based Drug-Drug Interaction Between Vonoprazan and Clopidogrel.

Background And Objectives: It was recently proposed that CYP-mediated drug-drug interactions (DDIs) of vonoprazan with clopidogrel and prasugrel can attenuate the antiplatelet actions of the latter two drugs. Clopidogrel is metabolized to the pharmacologically active metabolite H4 and its isomers by multiple CYPs, including CYP2C19 and CYP3A4. Therefore, to investigate the possibility of CYP-based DDIs, in vitro metabolic inhibition studies using CYP probe substrates or radiolabeled clopidogrel and human liver microsomes (HLMs) were conducted in this work.

Application of pharmacometric approaches to evaluate effect of weight and renal function on pharmacokinetics of alogliptin.

Aims: The aims of the study were to characterize the pharmacokinetics (PK) of alogliptin in healthy and type 2 diabetes mellitus (T2DM) subjects using a population PK approach and to assess the influence of various covariates on alogliptin exposure.

Methods: Plasma concentration data collected from two phase 1 studies and one phase 3 study following administration of alogliptin (12.5-400 mg) were used for the PK model development.

Effects of Peginesatide Injection on QTc Interval in Healthy Adults.

A single-dose, randomized, double-blind, placebo- and positive-controlled, three-period crossover study was conducted to evaluate the effect of peginesatide injection on QT interval in healthy adults. Subjects received single doses of placebo, peginesatide injection 0.1 mg/kg intravenous, or moxifloxacin 400 mg during three treatment periods, separated by 14-day washout intervals.

Gender-based differences in pharmacokinetics in laboratory animal models.

The study of gender-based differences in the pharmacokinetics (PK) of compounds tested in animal models has received greater attention in recent years. As early as 1932, the pharmacological action of barbiturates was recognized as gender dependent-female rats required half the dose needed by male rats to induce sleep. Later, it was shown that gender differences in hepatic metabolism were responsible for this gender-related pharmacodynamic response.

Assay of 1-nitropropane, 2-nitropropane, 1-azoxypropane and 2-azoxypropane for carcinogenicity by gavage in Sprague-Dawley rats.

1-Nitropropane (1-NP), 2-nitropropane (2-NP), 1-azoxypropane (1-AP) and 2-azoxypropane (2-AP), were assayed for carcinogenicity by gavage in male Sprague-Dawley rats. 2-NP was given at 1 mmol/kg three times per week for 16 weeks. 1-NP (1 mmol/kg), 1-AP (0.

Differential effects of 4-iodopyrazole and 3-methylpyrazole on the metabolic activation of methylazoxymethanol to a DNA methylating species by rat liver and rat colon mucosa in vivo.

Using a hybrid ion-exchange reverse phase HPLC system, we found that F344 rat liver microsomes, in the presence of an NADPH-generating system, can metabolize methylazoxymethanol (MAM), a colon and liver carcinogen, to methanol and formic acid. This is in contrast to the spontaneous decomposition of MAM which yields methanol and formaldehyde. The metabolism of MAM by rat liver microsomes is sensitive to inhibition by carbon monoxide as well as to inhibition by 3-methylpyrazole (3-MeP) and 4-iodopyrazole (4-IP), with 4-IP being more potent in this respect than 3-MeP.

Natural quinones as quinonemethide precursors--ideas in rational drug design.

The concept of the mode of biological action of quinones as bioreductive alkylating agents is presented. The focus of this discussion is primarily upon the structural features which would facilitate quinonemethide formation (alkylating agent) from the reduced quinone (hydroquinone). A survey of the naturally occurring quinone field was carried out and those members which can be catalogued as potential bioreductive alkylating agents are listed.