Preclinical Pharmacokinetics and Safety of Intravenous RTD-1

Abstract

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 (1). Rhesus theta (θ) defensin-1 (RTD-1) is a macrocyclic host defense peptide exhibiting antimicrobial and immunomodulatory activities. RTD-1 treatment significantly improved survival in murine models of a severe acute respiratory syndrome (SARS-CoV-1) and endotoxin-induced acute lung injury (ALI) (2, 3). This investigation aimed to characterize the preclinical pharmacokinetics and safety of intravenous (i.v.) RTD-1. Based on the lack of adverse findings, the no-observed-adverse-effect-level (NOAEL) was established at 10 mg/kg/day in rats and 15 mg/kg/day in monkeys. Analysis of single ascending dose studies in both species revealed greater than dose-proportional increases in area under the curve (AUC 0-∞ ), (e.g. 8-fold increase from 5 mg/kg to 20 mg/kg in rats) suggestive of nonlinear PK. The volume of distribution (Vss) ranged between 550 and 1,461 mL/kg, indicating extensive tissue distribution, which was validated in a biodistribution study of [ 14 C]-RTD-1 in rats. Based on interspecies allometric scaling, the predicted human clearance and Vss are 6.48 L/h and 28.0 L for an adult (70 kg). To achieve plasma exposures associated with therapeutic efficacy established in a murine model of ALI, the estimated human equivalent dose (HED) is between 0.36 and 0.83 mg/kg/day. The excellent safety profile demonstrated in these studies, and the efficacy observed in the murine models support the clinical investigation of RTD-1 for the treatment of COVID-19 or other pulmonary inflammatory diseases.

Turmeric and Onion Extracts as Effective Marinating Agents: Reducing PhIP Formation and Improving Quality in Cooked Chicken Breast across Various Cooking Techniques

“…These values are comparable to those obtained by [17]. Park et al [14] found that the pH of marinated pork was likewise shown to be somewhat acidic. The pork belly was marinated in various concentrations of green tea and yerba mate.…”

“…Additionally, ready-to-eat foods may benefit from the application of turmeric extracts as natural preservatives [13]. In fortified beverages and milk as colloidal food models, the usage of turmeric extract has also been investigated as nanopolisomes and nanoemulsions loaded, which act as antioxidants and antimicrobials [14]. Nowadays, various studies have concentrated on creating and analyzing edible films that include curcumin as a bioactive substance because of its antibacterial and antioxidant qualities [15].…”

Small molecules in the treatment of COVID-19

“…The cyclopeptide RTD-1, which has anti-SARS-CoV effects, was found to be safe to support its investigation for treatment of COVID-19. 530 …”

An ADAM10 Exosite Inhibitor Is Efficacious in an In Vivo Collagen-Induced Arthritis Model

“…To the best of our knowledge, there are no selective ADAM10-targeted RA therapies on the market or in development. RTD-1, a macrocyclic peptide inhibitor of ADAM17, is currently being evaluated by Oryn Therapeutics [ 15 , 16 , 17 ]. Disease-modifying small molecule anti-rheumatic drugs (DMARDs) approved or under evaluation for therapy in RA include Janus kinase (JAK) inhibitors, TNF inhibitors, T cell co-stimulation blockers, IL-6 receptor inhibitors, promoters of B cell depletion, and interleukin 1 inhibitors.…”