Pharmacokinetics, disposition, and biotransformation of the cardiac myosin inhibitor aficamten in humans.

Aficamten, a cardiac myosin inhibitor, is being developed for the treatment of patients with symptomatic hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine the absorption, metabolism, and excretion of aficamten. Eight healthy male participants received a single oral dose of 20 mg aficamten (containing approximately 100 μCi of radiocarbon).

Switching to tenofovir alafenamide in patients with virologically suppressed chronic hepatitis B and renal or hepatic impairment: final week 96 results from an open-label, multicentre, phase 2 study.

Background: Phase 3 studies in patients with chronic hepatitis B have shown tenofovir alafenamide to have non-inferior efficacy to tenofovir disoproxil fumarate, with improved renal and bone safety. We conducted this study to evaluate the safety and efficacy of switching to tenofovir alafenamide in participants with chronic hepatitis B and renal or hepatic impairment.

Methods: This open-label, multicentre, phase 2 study was done in eight countries or territories at 30 sites.

The Effect of a Quality Improvement Project on Improving Patients' Willingness to Receive an Influenza Vaccination in the Emergency Department.

The aim of this project was to increase willingness to receive the influenza vaccine to the optimal rate of ≥ 70%. Low acuity adult patients who visited an Emergency Department (ED) were assessed regarding their willingness to receive the influenza vaccine before and after an educational intervention that included a provider recommendation and an educational handout. A total of seventy-six patients (n = 76) were assessed.

Antiproliferative and Antimetastatic Properties of 16-Azidomethyl Substituted 3--Benzyl Estrone Analogs.

Four diastereomers of 16-azidomethyl substituted 3--benzyl estradiol (-) and their two estrone analogs ( and ) were tested for their antiproliferative properties against human gynecological cancer cell lines. The estrones were selected for additional experiments based on their outstanding cell growth-inhibiting activities. Both compounds increased hypodiploid populations of breast cancer cells, and elicited cell cycle disturbance as evidenced by flow cytometry.

Investigation of Anticancer Properties of Monoterpene-Aminopyrimidine Hybrids on A2780 Ovarian Cancer Cells.

The present study aimed to characterize the antiproliferative and antimetastatic properties of two recently synthesized monoterpene-aminopyrimidine hybrids ( and ) on A2780 ovary cancer cells. Both agents exerted a more pronounced cell growth inhibitory action than the reference agent cisplatin, as determined by the MTT assay. Tumor selectivity was assessed using non-cancerous fibroblast cells.

Prolonged activity of the transposase helper may raise safety concerns during DNA transposon-based gene therapy.

DNA transposon-based gene delivery vectors represent a promising new branch of randomly integrating vector development for gene therapy. For the side-by-side evaluation of the c and systems-the only DNA transposons currently employed in clinical trials-during therapeutic intervention, we treated the mouse model of tyrosinemia type I with liver-targeted gene delivery using both transposon vectors. For genome-wide mapping of transposon insertion sites we developed a new next-generation sequencing procedure called streptavidin-based enrichment sequencing, which allowed us to identify approximately one million integration sites for both systems.

A randomized controlled trial of presatovir for respiratory syncytial virus after lung transplant.

Background: Respiratory syncytial virus (RSV) infection in lung transplant recipients is associated with high morbidity. This study evaluated the RSV fusion inhibitor presatovir in RSV-infected lung transplant recipients.

Methods: In this international Phase 2b, randomized, double-blind, placebo-controlled trial (NCT02534350), adult lung transplant recipients with symptomatic confirmed RSV infection for ≤7 days received oral presatovir 200 mg on day 1 and 100 mg daily on days 2 to 14, or placebo (2:1), with follow-up through day 28.

A versatile transposon-based technology to generate loss- and gain-of-function phenotypes in the mouse liver.

Background: Understanding the contribution of gene function in distinct organ systems to the pathogenesis of human diseases in biomedical research requires modifying gene expression through the generation of gain- and loss-of-function phenotypes in model organisms, for instance, the mouse. However, methods to modify both germline and somatic genomes have important limitations that prevent easy, strong, and stable expression of transgenes. For instance, while the liver is remarkably easy to target, nucleic acids introduced to modify the genome of hepatocytes are rapidly lost, or the transgene expression they mediate becomes inhibited due to the action of effector pathways for the elimination of exogenous DNA.

Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor.

Remdesivir (RDV, Veklury) is a once-daily, nucleoside ribonucleic acid polymerase inhibitor of severe acute respiratory syndrome coronavirus 2 replication. Remdesivir has been granted approvals in several countries for use in adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). Inside the cell, remdesivir undergoes metabolic activation to form the intracellular active triphosphate metabolite, GS-443902 (detected in peripheral blood mononuclear cells), and ultimately, the renally eliminated plasma metabolite GS-441524.

Validation of LC-MS/MS methods for determination of remdesivir and its metabolites GS-441524 and GS-704277 in acidified human plasma and their application in COVID-19 related clinical studies.

Remdesivir (RDV) is a phosphoramidate prodrug designed to have activity against a broad spectrum of viruses. Following IV administration, RDV is rapidly distributed into cells and tissues and simultaneously metabolized into GS-441524 and GS-704277 in plasma. LC-MS/MS methods were validated for determination of the 3 analytes in human plasma that involved two key aspects to guarantee their precision, accuracy and robustness.

Physiologically-Based Pharmacokinetic Modeling of Remdesivir and Its Metabolites to Support Dose Selection for the Treatment of Pediatric Patients With COVID-19.

Severe coronavirus disease 2019 (COVID-19) disease, including multisystem inflammatory syndrome, has been reported in children. This report summarizes development of a remdesivir physiologically-based pharmacokinetic (PBPK) model that accurately describes observed adult remdesivir and metabolites exposure and predicts pediatric remdesivir and metabolites exposure. The adult PBPK model was applied to predict pediatric remdesivir and metabolites steady-state exposures using the Pediatric Population Model in SimCYP and incorporated the relevant physiologic and mechanistic information.

Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus-1.

Background: Treatment with vesatolimod, an investigational, oral, toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a Phase Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1.

Methods: In this double-blind, multicenter, placebo-controlled trial, participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose-escalation cohorts.

Safety, pharmacokinetics and pharmacodynamics of selgantolimod, an oral Toll-like receptor 8 agonist: a Phase Ia study in healthy subjects.

Background: Selgantolimod is a novel oral, selective Toll-like receptor 8 (TLR8) agonist in development for the treatment of chronic hepatitis B (CHB). TLR8 is an endosomal innate immune receptor and a target for treatment of viral infections. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selgantolimod in healthy volunteers.

Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, in Healthy Subjects.

Remdesivir (RDV), a single diastereomeric monophosphoramidate prodrug that inhibits viral RNA polymerases, has potent in vitro antiviral activity against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). RDV received the US Food and Drug Administration (FDA)'s emergency use authorization in the United States and approval in Japan for treatment of patients with severe coronavirus disease 2019 (COVID-19). This report describes two phase I studies that evaluated the safety and pharmacokinetics (PKs) of single escalating and multiple i.

An LC-MS/MS method for determination of tenofovir (TFV) in human plasma following tenofovir alafenamide (TAF) administration: Development, validation, cross-validation, and use of formic acid as plasma TFV stabilizer.

Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are both tenofovir (TFV) prodrugs, with the same active intracellular metabolite, TFV-diphosphate (TFV-DP). TAF delivers TFV-DP to target cells more efficiently and at lower doses than TDF, thereby substantially reducing systemic exposure to TFV, which results in improved bone and renal safety relative to TDF. As such, the method developed for the determination of TFV following TAF administration involved two key differences from determination of TFV following TDF administration.

The Drug-Drug Interaction Potential of Antiviral Agents for the Treatment of Chronic Hepatitis C Infection.

Several safe and highly effective direct-acting antiviral (DAA) drugs for chronic hepatitis C virus (HCV) have been developed and greatly increase the number of therapeutic options available to successfully treat HCV infection. However, because treatment regimens contain at least two drugs (e.g.

Phase 1 First-in-Human, Single- and Multiple-Ascending Dose, and Food Effect Studies to Assess the Safety, Tolerability, and Pharmacokinetics of Presatovir for the Treatment of Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV)-associated respiratory tract infection is a leading cause of hospitalizations in infants for which no effective treatment exists. RSV infection is also an important cause of respiratory disease in adults and immunocompromised patients. Presatovir (GS-5806) is an orally bioavailable antiviral agent that inhibits fusion of RSV with host cell membranes.

Drug-Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir.

Ledipasvir/sofosbuvir (Harvoni), a fixed-dose combination tablet of an NS5A inhibitor ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved for the treatment of chronic hepatitis C virus infection. Ledipasvir/sofosbuvir exhibits a favorable drug-drug interaction profile and can be administered with various medications that may be used by hepatitis C virus-infected patients, including patients with comorbidities, such as co-infection with human immunodeficiency virus or immunosuppression following liver transplantation. Ledipasvir/sofosbuvir is not expected to act as a victim or perpetrator of cytochrome P450- or UDP-glucuronosyltransferase 1A1-mediated drug-drug interactions.

Sofosbuvir plus ribavirin with or without peginterferon for the treatment of hepatitis C virus: Results from a phase 3b study in China.

Background And Aim: Sofosbuvir is a nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase with pangenotypic potency. This phase 3b study evaluated the safety and efficacy of sofosbuvir + ribavirin ± peginterferon in Chinese patients infected with HCV genotype 1, 2, 3, or 6.

Methods: Patients with genotype 1 or 6 received sofosbuvir + peginterferon/ribavirin for 12 weeks or sofosbuvir + ribavirin for 24 weeks, depending on prior treatment and interferon eligibility.

A Thorough QT Study to Evaluate the Effects of Supratherapeutic Doses of Ledipasvir on the QTc Interval in Healthy Subjects.

This study evaluated the effect of supratherapeutic exposure of the anti-HCV drug ledipasvir on the QTc interval in healthy subjects. Sixty healthy volunteers were randomized to receive twice-daily blinded ledipasvir (120 mg) or placebo, administered for 10 days each, or single doses of open-label moxifloxacin (400 mg). Serial plasma samples for ledipasvir concentration analysis were collected after each treatment.

HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas.

Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression.

Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects.

Preclinical characterization of velpatasvir (VEL; GS-5816), an inhibitor of the hepatitis C virus (HCV) NS5A protein, demonstrated that it has favorable and properties, including potent antiviral activity against hepatitis C virus genotype 1 to 6 replicons, good metabolic stability, low systemic clearance, and adequate bioavailability and physicochemical properties, to warrant clinical evaluation. The phase 1 (first-in-human) study evaluated the safety, tolerability, and pharmacokinetics of VEL in healthy human subjects following administration of single and multiple ( = 7) once-daily ascending doses and of VEL in the presence and absence of food. Following administration of single and multiple doses, VEL was safe and well tolerated when administered at up to 450 mg and when administered with food.