Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.

Dose Selection for Phase III Clinical Evaluation of Gepotidacin (GSK2140944) in the Treatment of Uncomplicated Urinary Tract Infections

Antibiotics are the current standard of care treatment for uncomplicated urinary tract infections (uUTIs). However, increasing rates of bacterial antibiotic resistance necessitate novel therapeutic options. Gepotidacin is a first-in-class triazaacenaphthylene antibiotic that selectively inhibits bacterial DNA replication by interaction with the bacterial subunits of DNA gyrase (GyrA) and topoisomerase IV (ParC). Gepotidacin is currently in clinical development for the treatment of uUTIs and other infections. In this article, we review data for gepotidacin from nonclinical studies including: in-vitro activity, in-vivo animal efficacy, and pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) models that informed dose selection for phase III clinical evaluation of gepotidacin. Based on this translational package of data, a gepotidacin 1,500 mg oral dose twice-daily for 5 days was selected for two ongoing, randomized, multicenter, parallel-group, double-blind, double-dummy, active-comparator phase III clinical studies evaluating the safety and efficacy of gepotidacin in adolescent and adult female participants with uUTIs (NCT04020341 and NCT04187144).

Meta-analysis of dose selection for budesonide in the treatment of Chinese patients with AECOPD

Published in August 2021

Physiologically Based Pharmacokinetic Modeling of Cefadroxil in Mouse, Rat, and Human to Predict Concentration–Time Profile at Infected Tissue

The aim of this study was to develop physiologically based pharmacokinetic (PBPK) models capable of simulating cefadroxil concentrations in plasma and tissues in mouse, rat, and human. PBPK models in this study consisted of 14 tissues and 2 blood compartments. They were established using measured tissue to plasma partition coefficient (Kp) in mouse and rat, absolute expression levels of hPEPT1 along the entire length of the human intestine, and the transporter kinetic parameters. The PBPK models also assumed that all the tissues were well-stirred compartments with perfusion rate limitations, and the ratio of the concentration in tissue to the unbound concentration in plasma is identical across species. These PBPK models were validated strictly by a series of observed plasma concentration–time profile data. The average fold error (AFE) and absolute average fold error (AAFE) values were all less than 2. The models’ rationality and accuracy were further demonstrated by the almost consistent Vss calculated by the PBPK model and noncompartmental method, as well as the good allometric scaling relationship of Vss and CL. The model suggests that hPEPT1 is the major transporter responsible for the oral absorption of cefadroxil in human, and the plasma concentration–time profiles of cefadroxil were not sensitive to dissolution rate faster than T85% = 2 h. The cefadroxil PBPK model in human is reliable and can be used to predict concentration–time profile at infected tissue. It may be useful for dose selection and informative decision-making during clinical trials and dosage form design of cefadroxil and provide a reference for the PBPK model establishment of hPEPT1 substrate.

The Research Progress of PD-1/PD-L1 Inhibitors Enhancing Radiotherapy Efficacy

Approximately 60%–70% of patients with malignant tumours require radiotherapy. The clinical application of immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1, has revolutionized cancer treatment and greatly improved the outcome of a variety of cancers by boosting host immunity.However, radiotherapy is a double-edged sword for PD-1/PD-L immunotherapy. Research on how to improve radiotherapy efficacy using PD-1/PD-L1 inhibitor is gaining momentum. Various studies have reported the survival benefits of the combined application of radiotherapy and PD-1/PD-L1 inhibitor. To fully exerts the immune activation effect of radiotherapy, while avoiding the immunosuppressive effect of radiotherapy as much as possible, the dose selection, segmentation mode, treatment timing and the number of treatment sites of radiotherapy play a role. Therefore, we aim to review the effect of radiotherapy combined with anti-PD-1/PD-L1 on the immune system and its optimization.

Pharmacodynamics and the Bactericidal Activity of Bedaquiline in Pulmonary Tuberculosis

Bedaquiline is a diarylquinoline antimycobacterial drug and a key component of several regimens in clinical development for treatment of tuberculosis (TB), but with ongoing phase 3 trials that include assessment of simplified dosing. A pharmacokinetic-pharmacodynamic model of bedaquiline Mycobacterium tuberculosis killing kinetics in adults with pulmonary TB was developed to inform dose selection of bedaquiline-containing regimens. The model parameters were estimated with data from the 14-day early bactericidal activity (EBA) study TMC207-CL001 conducted in Cape Town, South Africa. The study included 60 adult males and females with drug-susceptible pulmonary TB, who were administered bedaquiline with loading doses on the first two days followed by once daily 100 mg, 200 mg, 300 mg, or 400 mg. The modeling results included expected values (mean±SD) for a maximum drug kill rate constant equal to 0.23±0.03 log 10 CFU/mL sputum/day, a half-maximum effect plasma concentration equal to 1.6±0.3 mg/L, and an average time to onset of activity equal to 40±7 h. Model simulations showed once daily 200 mg, 300 mg, and 400 mg (without loading doses) attained 40%, 50%, and 60%, respectively, of an expected maximum 14-day EBA equal to 0.18 log 10 CFU/mL/day, or 10 h/day assessed by liquid culture time to positivity (TTP). Additional simulations illustrated efficacy outcomes during eight weeks of treatment with the recommended and alternative dosages. The results demonstrate a general mathematical and statistical approach to analysis of EBA studies with broad application to TB regimen development.