Rethinking the Role of Clinical Pharmacology in a Systems Perspective to Accelerate Small Molecules (Entry, Protease and Polymerase Inhibitors) Development

Quickly defining this new virus, scientists and physicians have worked in an unprecedented common effort against this disease. Since its discovery in 2019, SARS-CoV-2 is not yet defeated. Likely we will have to co-exist like the other Influenzas A viruses for a long while; furthermore, the role of drugs in the so-called “long” COVID is still unexplored, yet much needed. Thanks to the unprecedented Systems thinking with the integration of modern approaches and systemic knowledge from many fields, we understood, quite rapidly, the key points to attack the virus via pharmacological strategies: for vaccines the Spike protein, or antivirals the accessory proteins like proteases (eg, Mpro) and the polymerase (RdRp). Antivirals hold the potential to be effective in the early stages of infection, or as preventive strategies. First, antivirals were conveniently repositioned from HIV or MERS, such as lopinavir (Asia) or remdesivir (America). Dosing and target concentrations, in adults and pediatrics, were studied by PBPK models associated with viral kinetic dynamic models. It allowed the smart design of regimens accounting for the balance between safety and potential efficacy (eg, IVIV IC90-based extrapolations). Repositioning was most successful if integrated with Systems thinking. Similarly, efforts in developing new antivirals had started. 2 antivirals gained approval and some usages: the protease inhibitor nirmatrelvir/ritonavir (oral-Paxlovid) and the polymerase inhibitor molnupinavir (oral). Having an HIV background, we studied the antiviral strategy in COVID19 and came to the following conclusions: at the early stages, the best small molecules are antivirals targeting the protease inhibitors and the RdRp, ideally in combination. The viral load can then be curbed while the immune systems mature (either from a vaccine or for the first time) to organize a response. Concluding that other large molecules might be more potent, such as mAb, antivirals targeting those two viral enzymes seem to be very resistant to mutations and therefore variants, effectively giving long-term usability of antivirals. 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 – or at most – we have learned the importance to empower these models and analytical tools for a next pandemics.