Calibration and Validation of a Mechanistic COVID-19 Model for Translational Quantitative Systems Pharmacology - A Proof-of-Concept Model Development for Remdesivir.

With the ongoing global pandemic of coronavirus disease 2019 (COVID-19), there is an urgent need to accelerate the traditional drug development process. Many studies identified potential COVID-19 therapies based on promising nonclinical data. However, the poor translatability from nonclinical to clinical settings has led to failures of many of these drug candidates in the clinical phase. In this study, we propose a mechanism-based, quantitative framework to translate nonclinical findings to clinical outcome. Adopting a modularized approach, this framework includes an in silico disease model for COVID-19 (virus infection and human immune responses) and a pharmacological component for COVID-19 therapies. The disease model was able to reproduce important longitudinal clinical data for patients with mild and severe COVID-19, including viral titer, key immunological cytokines, antibody responses, and time courses of lymphopenia. Using remdesivir as a proof-of-concept example of model development for the pharmacological component, we developed a pharmacological model that describes the conversion of intravenously administered remdesivir as a prodrug to its active metabolite nucleoside triphosphate through intracellular metabolism and connected it to the COVID-19 disease model. After being calibrated with the placebo arm data, our model was independently and quantitatively able to predict the primary endpoint (time to recovery) of the remdesivir clinical study, Adaptive Covid-19 Clinical Trial (ACTT). Our work demonstrates the possibility of quantitatively predicting clinical outcome based on nonclinical data and mechanistic understanding of the disease and provides a modularized framework to aid in candidate drug selection and clinical trial design for COVID-19 therapeutics.

Plasmapheresis: a feasible choice for bullous pemphigoid patients infected with SARS-CoV-2.

Bullous pemphigoid (BP) patients were vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection because they have similar risk factors, so we should pay attention to patients with BP during the epidemic of coronavirus disease-19 (COVID-19). As far as treatment is concerned, many strategies for BP were changed during the epidemic. Plasmapheresis not only has been included in the guidelines for BP but also has been used successfully to rescue COVID-19 patients, especially in severe cases. Therefore, it is a feasible choice for BP patients, especially for refractory BP patients, infected with SARS-CoV-2. Apart from these, we have reviewed some points for attention during the plasmapheresis session.