Pharmacokinetics of Omadacycline in Adults with Cystic Fibrosis.

Background: Omadacycline offers a potential advancement in the management of infections in people with cystic fibrosis (CF) because of its spectrum of activity, intrapulmonary penetration, and oral bioavailability. A prospective single-dose, single-arm study was conducted to characterize the pharmacokinetic (PK) profile of omadacycline in people with CF, considering the known alterations in PK observed in this population (NCT04460586, 2020-07-01).

Methods: Plasma samples were obtained from nine adults with CF who received a single dose of intravenous omadacycline 100 mg over 0.

Immunomodulatory activity of omadacycline and in a murine model of acute lung injury.

Cystic fibrosis (CF) is characterized by chronic airway obstruction, infection, and inflammation leading to progressive loss of lung function and eventual respiratory failure. Omadacycline, a tetracycline antibiotic, demonstrates activity against key CF pathogens, substantial lung penetration, and increasing clinical evidence for the treatment of lung infections in people with CF (PwCF). Preliminary data demonstrate that omadacycline exhibits anti-inflammatory activity.

Drug-induced liver injury associated with elexacaftor/tezacaftor/ivacaftor: A pharmacovigilance analysis of the FDA adverse event reporting system (FAERS).

Introduction: The efficacy and safety of elexacaftor/tezacaftor/ivacaftor (ETI) have been established in prospective clinical trials. Liver function test elevations were observed in a greater proportion of patients receiving ETI compared with placebo; however, the relatively small number of patients and short duration of study preclude detection of rare but clinically significant associations with drug-induced liver injury (DILI). To address this gap, we assessed the real-world risk of DILI associated with ETI through data mining of the FDA adverse event reporting system (FAERS).

Preliminary evidence for sustained efficacy of CFTR modulator therapy with concomitant rifabutin administration.

The concomitant use of elexacaftor/tezacaftor/ivacaftor (ETI) and strong CYP3A inducers including rifampin and rifabutin is not recommended due to the risk of drug-drug interactions (DDI). This presents a significant challenge to the treatment of non-tuberculous mycobacteria precluding the first line treatment. While rifabutin induces CYP3A activity, its effect appears to be moderate compared to rifampin.

Drug-drug interactions involving CFTR modulators: a review of the evidence and clinical implications.

Introduction: Cystic fibrosis (CF) is characterized by mucus accumulation impairing the lungs, gastrointestinal tract, and other organs. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators (ivacaftor, tezacaftor, elexacaftor, and lumacaftor) significantly improve lung function and nutritional status; however, they are substrates, inhibitors, and/or inducers of certain CYP enzymes and transporters, raising the risk of drug-drug interactions (DDI) with common CF medications.

Areas Covered: A literature search was conducted for DDIs involving CFTR modulators by reviewing new drug applications, drug package inserts, clinical studies, and validated databases of substrates, inhibitors, and inducers.

Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions between Elexacaftor/Tezacaftor/Ivacaftor and Tacrolimus in Lung Transplant Recipients.

Elexacaftor/tezacaftor/ivacaftor (ETI) treatment has potential benefits in lung transplant recipients, including improvements in extrapulmonary manifestations, such as gastrointestinal and sinus disease; however, ivacaftor is an inhibitor of cytochrome P450 3A (CYP3A) and may, therefore, pose a risk for elevated systemic exposure to tacrolimus. The aim of this investigation is to determine the impact of ETI on tacrolimus exposure and devise an appropriate dosing regimen to manage the risk of this drug-drug interaction (DDI). The CYP3A-mediated DDI of ivacaftor-tacrolimus was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach, incorporating CYP3A4 inhibition parameters of ivacaftor and in vitro enzyme kinetic parameters of tacrolimus.

Safety of elexacaftor/tezacaftor/ivacaftor dose reduction: Mechanistic exploration through physiologically based pharmacokinetic modeling and a clinical case series.

Introduction: Elexacaftor/tezacaftor/ivacaftor (ETI) treatment is associated with significant improvement in lung function in people with cystic fibrosis (pwCF); however, some patients experience adverse effects (AEs) including hepatotoxicity. One potential strategy is dose reduction in ETI with the goal of maintaining therapeutic efficacy while resolving AEs. We report our experience of dose reduction in individuals who experienced AEs following ETI therapy.

Physiologically Based Pharmacokinetic Modeling To Guide Management of Drug Interactions between Elexacaftor-Tezacaftor-Ivacaftor and Antibiotics for the Treatment of Nontuberculous Mycobacteria.

Nontuberculous mycobacteria (NTM) are the pathogens of concern in people with cystic fibrosis (pwCF) due to their association with deterioration of lung function. Treatment requires the use of a multidrug combination regimen, creating the potential for drug-drug interactions (DDIs) with cystic fibrosis transmembrane conductance regulator (CFTR)-modulating therapies, including elexacaftor, tezacaftor, and ivacaftor (ETI), which are eliminated mainly through cytochrome P450 (CYP) 3A-mediated metabolism. An assessment of the DDI risk for ETI coadministered with NTM treatments, including rifabutin, clofazimine, and clarithromycin, is needed to provide appropriate guidance on dosing.

Physiologically-Based Pharmacokinetic-Led Guidance for Patients With Cystic Fibrosis Taking Elexacaftor-Tezacaftor-Ivacaftor With Nirmatrelvir-Ritonavir for the Treatment of COVID-19.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies, including elexacaftor-tezacaftor-ivacaftor, are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of coronavirus disease 2019 (COVID-19) with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDIs). However, the population with CF is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options.

Preclinical Pharmacokinetics and Safety of Intravenous RTD-1.

Severe illness caused by coronavirus disease 2019 (COVID-19) is characterized by an overexuberant inflammatory response resulting in acute respiratory distress syndrome (ARDS) and progressive respiratory failure (A. Gupta, M. V.

Chemical Synthesis of a Potent Antimicrobial Peptide Murepavadin Using a Tandem Native Chemical Ligation/Desulfurization Reaction.

Classical approaches for the backbone cyclization of polypeptides require conditions that may compromise the chirality of the C-terminal residue during the activation step of the cyclization reaction. Here, we describe an efficient epimerization-free approach for the Fmoc-based synthesis of murepavadin using intramolecular native chemical ligation in combination with a concomitant desulfurization reaction. Using this approach, bioactive murepavadin was produced in a good yield in two steps.

Anti-Inflammatory Effects of RTD-1 in a Murine Model of Chronic Lung Infection: Inhibition of NF-κB, Inflammasome Gene Expression, and Pro-IL-1β Biosynthesis.

Vicious cycles of chronic airway obstruction, lung infections with , and neutrophil-dominated inflammation contribute to morbidity and mortality in cystic fibrosis (CF) patients. Rhesus theta defensin-1 (RTD-1) is an antimicrobial macrocyclic peptide with immunomodulatory properties. Our objective was to investigate the anti-inflammatory effect of RTD-1 in a murine model of chronic lung infection.

Engineered Cyclotides with Potent Broad in Vitro and in Vivo Antimicrobial Activity.

The search for novel antimicrobial agents to combat microbial pathogens is intensifying in response to the rapid development of drug resistance to current antibiotic therapeutics. Respiratory failure and septicemia are the leading causes of mortality among hospitalized patients. Here, the development of a novel engineered cyclotide with effective broad-spectrum antibacterial activity against several ESKAPE bacterial strains and clinical isolates is reported.

Enhanced brain delivery and therapeutic activity of trastuzumab after blood-brain barrier opening by NEO100 in mouse models of brain-metastatic breast cancer.

Background: The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity.

Rhesus Theta Defensin 1 Promotes Long Term Survival in Systemic Candidiasis by Host Directed Mechanisms.

Invasive candidiasis is an increasingly frequent cause of serious and often fatal infections in hospitalized and immunosuppressed patients. Mortality rates associated with these infections have risen sharply due to the emergence of multidrug resistant (MDR) strains of C. albicans and other Candida spp.

The Potential for QT Interval Prolongation with Chronic Azithromycin Therapy in Adult Cystic Fibrosis Patients.

Introduction: Oral azithromycin (AZM) has been shown to reduce airway inflammation and disrupt biofilm formation. However, chronic AZM therapy may result in QT interval (QTc) prolongation.

Objectives: The goals of this study were twofold: (i) to characterize the risk of QTc prolongation in adult patients with cystic fibrosis (CF) receiving AZM and other potential QTc-prolonging agents, and (ii) to describe and capture the number of potential QTc-prolonging agents patients with CF are prescribed.

Pharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis.

Over the past decade, the prevalence of infections involving methicillin-resistant (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics have been shown to be altered in CF patients.

Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide.

θ-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkeys. The peptides are pleiotropic effectors of innate immunity, possessing broad spectrum antimicrobial activities and immunoregulatory properties. Here we report that rhesus θ-defensin 1 (RTD-1) is highly effective in arresting and reversing joint disease in a rodent model of rheumatoid arthritis (RA).

Rhesus θ-Defensin-1 Attenuates Endotoxin-induced Acute Lung Injury by Inhibiting Proinflammatory Cytokines and Neutrophil Recruitment.

Acute lung injury (ALI) is a clinical syndrome characterized by acute respiratory failure and is associated with substantial morbidity and mortality. Rhesus θ-defensin (RTD)-1 is an antimicrobial peptide with immunomodulatory activity. As airway inflammation and neutrophil recruitment and activation are hallmarks of ALI, we evaluated the therapeutic efficacy of RTD-1 in preclinical models of the disease.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis.

Acute pulmonary exacerbations (APE) involving are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent activity against isolates recovered from CF patients, including drug-resistant strains.

Efficacy of Rhesus Theta-Defensin-1 in Experimental Models of Pseudomonas aeruginosa Lung Infection and Inflammation.

Chronic airway infection and inflammation contribute to the progressive loss of lung function and shortened survival of patients with cystic fibrosis (CF). Rhesus theta defensin-1 (RTD-1) is a macrocyclic host defense peptide with antimicrobial and immunomodulatory activities. Combined with favorable preclinical safety and peptide stability data, RTD-1 warrants investigation to determine its therapeutic potential for treatment of CF lung disease.

Subregional laminar cartilage MR spin-spin relaxation times (T2) in osteoarthritic knees with and without medial femorotibial cartilage loss - data from the Osteoarthritis Initiative (OAI).

Objective: To explore whether subregional laminar femorotibial cartilage spin-spin relaxation time (T2) is associated with subsequent radiographic progression and cartilage loss and/or whether one-year change in subregional laminar femorotibial cartilage T2 is associated with concurrent progression in knees with established radiographic OA (ROA).

Methods: In this case-control study, Osteoarthritis Initiative (OAI) knees with medial femorotibial progression were selected based on one-year loss in both quantitative cartilage thickness Magnetic resonance imaging (MRI) and radiographic joint space width (JSW). Non-progressor knees were matched by sex, Body mass index (BMI), baseline Kellgren-Lawrence-grade (2/3), and pain.