Clinical Pharmacology – Biomolecular
.jpg "Simone Perazzolo, PhD photo")
Simone Perazzolo, PhD
Scientist
University of Washington
Southampton, England, United Kingdom
Since its discovery in 2019, with 555 million confirmed infections and 6.35 million deaths, SARS-CoV-2 is not yet defeated. However, thanks to the unprecedented Systems thinking with the integration of modern approaches we have been able to reopen and carry on socioeconomic activities. Clinically, Covid-19 presents flu-like symptoms that can exacerbate, in about 7-10 days from onset, into host non-antigen-specific and overreactive immunological responses referred to as “cytokine storm”, which leads to respiratory failure and death. While early implementation of public health approaches in social distancing, enhanced environment cleaning, and wearing personal protection equipment have helped to curb transmissions and death rates, these measures required significant disruption in normal life. Within months from viral isolation, we have witnessed rapid and systems-wide integration of basic, clinical, and pharmaceutical sciences to bring diagnostic, vaccine, and therapeutic interventions. The exponential growth in systems-wide knowledge on viral genetics, mechanisms of replication, disease development, and in the context of time-based progression is unmatched. Quantitative knowledge in the time-course of infection and host-antibody and cytokine responses has enabled defining targets for developing vaccines, drugs, antibodies, and cytokine modulators as well as innovations in clinical care in preventing COVID-19 disease course and death. It was early recognized that both vaccines and therapeutics were key in the fight against the pandemic. The launch of the COVID-19 vaccine happened in just 1 year. We had the viral target profiles, so thanks to proper national infrastructure and the drive to integrate basic, translational, non-clinical, and clinical research expertise, we were able to produce recombinant-based and lipid-based nanoparticles carrying mRNA to express S protein of SARS-CoV-2 antigen vaccines. With impressive speeds, neutralizing monoclonal antibodies (mAb) were developed as well. However, mAb are not consistently effective as frequent new S-protein-based variants evolve the virus (eg., Omicron-BA1-5). Coming from an HIV laboratory, we believe that small molecule antivirals will still be needed even with herd immunity, especially in combination. To date, 3 antivirals that gained approval and some usages are the protease inhibitor nirmatrelvir/ritonavir (oral-Paxlovid) and the polymerase inhibitors molnupinavir (oral) and remdesivir (IV-Velkury). All of them seem to retain antiviral activity against all variants discovered thus far. Quantitative Systems Pharmacology approaches may allow scientists to project how antivirals and the immunoregulatory agent could be evaluated optimally for this complex pandemic disuse. The dosage formulation and drug-drug interaction effects can be modeled to inform product development and testing to increase the clinical success rate. Antivirals will likely be effective at the early stages of infection - soon after exposure and before hospitalization. On the other hand, immunoregulatory agents should be used in the later stages of the disease, ie., those progressing toward the cytokine storms. The systems approach that integrates the quantitative and mechanistic understanding of viral-host interactions in time events combined with Quantitative Systems Pharmacology will continue to guide and improve our socioeconomic activities under the new normal COVID-19 endemics.