Pharmacokinetics of islatravir in participants with moderate hepatic impairment.

Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. People living with HIV are at risk of liver disease. ISL is metabolized by adenosine deaminase (ADA), which is expressed in the liver; thus, ISL pharmacokinetics (PK) may be affected by hepatic impairment.

Pharmacokinetics and bioequivalence of a molnupiravir tablet formulation compared with the molnupiravir capsule formulation in healthy adult participants-a randomized, open-label, three-period, crossover study.

Molnupiravir, a prodrug of β-D-N-hydroxycytidine (NHC), is administered orally as four 200 mg capsules twice daily for 5 days to treat COVID-19. This randomized, open-label, four-treatment sequence, three-period crossover study (NCT06615869) evaluated the bioequivalence of a new single 400 mg oral dose of the molnupiravir tablet Formulation 1 (F1) to a 400 mg oral dose of the currently authorized molnupiravir capsule formulation (administered as two 200 mg capsules) by comparing the plasma pharmacokinetics of NHC following administration to healthy participants. The effect of food on the plasma NHC pharmacokinetics following the administration of the molnupiravir F1 tablet, safety and tolerability of a single oral 400 mg dose of molnupiravir, and pharmacokinetics of a separate molnupiravir tablet Formulation 2 (F2) with a slower dissolution rate were also evaluated.

Nonclinical and clinical characterization of the absorption, metabolism, and excretion of islatravir.

The development of new and improved antiretroviral therapies that allow for alternative dosing schedules is needed for people living with HIV-1. Islatravir is a deoxyadenosine analog in development for the treatment of HIV-1 that suppresses HIV-1 replication via multiple mechanisms of action, including reverse transcriptase translocation inhibition and delayed chain termination. Islatravir is differentiated from other HIV-1 antiretrovirals by its high potency, long , broad tissue distribution, and favorable drug resistance profile.

A Phase 1 Study to Evaluate the Pharmacokinetic Drug-Drug Interaction Between Islatravir and Methadone in Participants on Stable Methadone Therapy.

Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment of HIV-1. People living with HIV-1 receiving methadone maintenance therapy may benefit from islatravir. This study was designed to evaluate single-dose islatravir on steady-state methadone pharmacokinetics.

Syndication in science: Curated collaboration.

Development and validation of digital measures require dedicated clinical studies, which can be conducted by a single study sponsor or a precompetitive collaboration. In this perspective, we propose an alternative model, data syndication, a curated collaboration, which foresees a technology provider being a founding member with biopharmaceutical sponsors and other stakeholders joining. Its main advantages are the speed of the study startup and the opportunity for real-time data streaming.

Assessment of pharmacokinetics and tolerability following single-dose administration of molnupiravir in participants with hepatic or renal impairment.

Individuals with chronic liver or kidney disease are at increased risk of severe COVID-19. Molnupiravir is an orally administered antiviral authorized for the treatment of mild-to-moderate COVID-19 in adults at risk of progression to severe disease. Two nonrandomized, open-label, single-dose, multicenter, phase 1 trials were conducted to investigate the effects of hepatic and renal impairment on the tolerability and pharmacokinetics of molnupiravir (800 mg) and its metabolite β-D-N4-hydroxycytidine (NHC; NCT05386589/NCT05386758).

Pharmacokinetics of Atorvastatin and Metformin after Coadministration with Islatravir in Healthy Adults.

Islatravir, a deoxyadenosine analog that inhibits HIV-1 replication by multiple mechanisms of action, including reverse transcriptase translocation inhibition, is being developed for use in HIV-1 treatment. People living with HIV often have comorbidities, such as dyslipidemia or type 2 diabetes mellitus, necessitating long-term concomitant drug therapy. This nonrandomized, two-period, fixed-sequence, open-label, phase 1, drug-drug interaction study was conducted to evaluate the effects of islatravir coadministration on atorvastatin and metformin pharmacokinetics (PK) in healthy adults.

A Randomized, Double-Blind, Placebo-Controlled, Short-Term Monotherapy Study of MK-6186, an HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor, in Treatment-Naïve HIV-Infected Participants.

To assess the antiviral activity, pharmacokinetics, and safety of MK-6186 in HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI)-naïve, HIV-1-infected male participants. Double-blind, randomized, two-panel study. In 2 sequential panels, 18 participants received MK-6186 (40 mg [Panel A] or 150 mg [Panel B]) or matching placebo once daily for 7 days.

Intracellular islatravir-triphosphate half-life supports extended dosing intervals.

Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t) of 3.

Gefapixant as a P2X3 receptor antagonist treatment for obstructive sleep apnea: a randomized controlled trial.

Study Objectives: Obstructive sleep apnea (OSA) is a highly prevalent disorder with serious health consequences but limited therapeutic options. For a subset of those with OSA, a key underlying mechanism is hypersensitive chemoreflex control of breathing. There is no approved therapy that targets this endotypic trait.

Thorough QT/QTc study to evaluate the effect of a single supratherapeutic dose of islatravir on QTc interval prolongation in healthy adults.

Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in combination with other antiretroviral therapies, at doses of 0.25 mg once daily and 2 mg once weekly.

Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate Cyclase Stimulator, in Participants with Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease.

Purpose: This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension associated with COPD (PH-COPD).

Methods: Eligible participants were 40-80 years old with COPD (FEV/FVC <0.7; FEV >30% predicted) and PH (mean pulmonary arterial pressure ≥25 mmHg).

Single- and Multiple-Dose Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist, in Healthy Adults.

Gefapixant (MK-7264, RO4926219, AF-219) is a first-in-class P2X3 antagonists being developed to treat refractory or unexplained chronic cough. The initial single- and multiple-dose safety, tolerability, and pharmacokinetics of gefapixant at doses ranging from 7.5 to 1800 mg were assessed in four clinical trials.

Pooled analysis of routine safety parameters observed in healthy participants at baseline and following placebo administration in early phase clinical studies.

Phase I trials inform on the initial safety profile of a new molecule and impact whether further development is pursued or not. Understanding the effect of non-pharmacological factors on the variability of routine safety parameters could improve decision making in these early clinical trials, helping to separate signals related to the new molecule from background "noise." To understand the impact of non-pharmacological factors on routine safety parameters, we evaluated pooled safety data from over 1000 healthy participants treated with placebo in phase I trials between 2009 and 2018.

Evaluation of a stabilized RSV pre-fusion F mRNA vaccine: Preclinical studies and Phase 1 clinical testing in healthy adults.

Human respiratory syncytial virus (RSV) causes a substantial proportion of respiratory tract infections worldwide. Although RSV reinfections occur throughout life, older adults, particularly those with underlying comorbidities, are at risk for severe complications from RSV. There is no RSV vaccine available to date, and treatment of RSV in adults is largely supportive.

Assessment of pharmacokinetics, safety, and tolerability following twice-daily administration of molnupiravir for 10 days in healthy participants.

Molnupiravir is an orally administered, small-molecule ribonucleoside prodrug of β-D-N4-hydroxycytidine (NHC) that has demonstrated potent, broad-spectrum preclinical activity against RNA viruses and has a high barrier to the development of resistance. A double-blind, placebo-controlled, phase I trial was conducted to evaluate the pharmacokinetics (PKs), safety, and tolerability of 10.5-day administration of multiple doses of molnupiravir and its metabolites in healthy, adult participants.

Considerations for Cell and Gene Therapy Programs Entering the Clinical Space.

Cell and gene therapy (CGT) describes a broad category of medicinal products with potential applications to prevent and treat human disease in multiple therapeutic areas. These therapies leverage the use of modified nucleic acids, altered cells or tissue, or both. The modality, mechanism, route of administration, and therapeutic indication for a CGT product will influence the challenges and opportunities for early clinical development, some of which may be highly specific to the product under consideration.

Evaluation of the inhibitory effects of itraconazole on letermovir.

Aims: Letermovir, a cytomegalovirus (CMV) DNA terminase complex inhibitor, is a substrate of ABCB1 (P-glycoprotein; P-gp), organic anion transporting polypeptide (OATP)1B1/3, UDP-glucuronosyltransferase (UGT)1A1, UGT1A3 and possibly ABCG2 (breast cancer resistance protein; BCRP). A study was conducted to evaluate the effects of itraconazole, a prototypic ABCB1/ABCG2 inhibitor, on letermovir pharmacokinetics (PK) and the effects of letermovir on itraconazole PK.

Methods: In an open-label, fixed-sequence study in 14 healthy participants, 200 mg oral itraconazole was administered once daily for 4 days.

A drug-drug interaction study with letermovir and acyclovir in healthy participants.

Letermovir inhibits renal tubular organic anion transporter 3 (OAT3) in vitro and is predicted to inhibit OAT3 in vivo. Acyclovir, a substrate for OAT3, is likely to be coadministered with letermovir; therefore, letermovir may increase acyclovir concentrations. A drug-drug interaction study was conducted in healthy participants (N = 16) to assess the effect of letermovir on acyclovir pharmacokinetics.

Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH).

Background: Novel therapeutics for pulmonary arterial hypertension (PAH) with improved safety/tolerability profiles are needed to address continued high rates of morbidity/mortality.

Methods: This Phase 1 study evaluated efficacy/safety of inhaled single-dose MK-5475, an investigational, small-molecule stimulator of soluble guanylate cyclase designed for inhaled delivery via a dry-powder inhaler device, in participants with PAH (Clinicaltrials.gov: NCT03744637).

A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial of Radiopaque Islatravir-Eluting Subdermal Implants for Pre-exposure Prophylaxis Against HIV-1 Infection.

Background: Islatravir (MK-8591) is a deoxyadenosine analog in development for the treatment and prevention of HIV-1 infection. An islatravir-eluting implant could provide an additional option for pre-exposure prophylaxis (PrEP).

Setting: Previous data support a threshold islatravir triphosphate concentration for PrEP of 0.

Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency.

Islatravir (MK-8591) is a high-potency reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. Data from preclinical and clinical studies suggest that ~30% to 60% of islatravir is excreted renally and that islatravir is not a substrate of renal transporters. To assess the impact of renal impairment on the pharmacokinetics of islatravir, an open-label phase 1 trial was conducted with individuals with severe renal insufficiency (RI).

Safety and immunogenicity of intramuscular, single-dose V590 (rVSV-SARS-CoV-2 Vaccine) in healthy adults: Results from a phase 1 randomised, double-blind, placebo-controlled, dose-ranging trial.

Background: Vaccines against COVID-19 are needed to overcome challenges associated with mitigating the global pandemic. We report the safety and immunogenicity of V590, a live recombinant vesicular stomatitis virus-based COVID-19 vaccine candidate.

Methods: In this placebo-controlled, double-blind, three-part phase 1 study, healthy adults were randomised to receive a single intramuscular dose of vaccine or placebo.