Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates

Over 50 million people have been infected with the SARS-CoV-2 virus, while around 1 million have died due to COVID-19 disease progression. COVID-19 presents flu-like symptoms that can escalate, in about 7–10 days from onset, into a cytokine storm causing respiratory failure and death. Although social distancing reduces transmissibility, COVID-19 vaccines and therapeutics are essential to regain socioeconomic normalcy. Even if effective and safe vaccines are found, pharmacological interventions are still needed to limit disease severity and mortality. Integrating current knowledge and drug candidates (approved drugs for repositioning among >35 candidates) undergoing clinical studies (>3000 registered in ClinicalTrials.gov), we employed Systems Pharmacology approaches to project how antivirals and immunoregulatory agents could be optimally evaluated for use. Antivirals are likely to be effective only at the early stage of infection, soon after exposure and before hospitalization, while immunomodulatory agents should be effective in the later-stage cytokine storm. As current antiviral candidates are administered in hospitals over 5–7 days, a long-acting combination that targets multiple SARS-CoV-2 lifecycle steps may provide a long-lasting, single-dose treatment in outpatient settings. Long-acting therapeutics may still be needed even when vaccines become available as vaccines are likely to be approved based on a 50% efficacy target.

Since its discovery in late 2019 as a novel pathogenetic coronavirus, the SARS-CoV-2 virus is far from being defeated. Owing to its high transmission rate, poorly recorded herd immunity, and an unclear possibility of re-infection, SARS-CoV-2 is projected to be eradicated in years. Therefore, effective pharmacological therapy is and will be the frontline to reduce infection rates and disease progression, especially for those who are exposed but not immune, regardless of the timing and availability of a vaccine. At early stages, effective antivirals are ideal for use in pre/post-exposure or at clinically mild symptom presentation. If antiviral therapy is insufficient or the disease has already progressed toward severity, immunomodulators should ameliorate the patient's over-reactive immune status. Thus, there are hundreds of ongoing clinical trials focusing on these two categories of drugs. To accelerate the timeline to access effective drugs, clinical trials are based on the idea of repositioning FDA-approved drugs from other indications. They should demonstrate inhibition of SARS-CoV-2 at plasma and lung concentrations that are achievable with currently recommended dosing. This PK-driven thinking is substantiated by the viral dynamic time-course we have collected: antivirals should flat the viral load curve before it peaks, while immunomodulators should reduce tissue damage caused by the cytokine storm. Therefore, antiviral therapy with prompt testing (assisted by AI-tools) is the best-positioned strategy to kill the virus before harming patients and avoiding subsequent ICUs clogging. Although remdesivir is the only recommended drug used in hospitalized patients, we have reasoned here that a lopinavir-ritonavir plus remdesivir combination might potentially offer the best antiviral option available at the moment (with the possibility of IFN-b supplementation, e.g., ACTT-3 trial, or TCM as adjuvant therapy). We supported this idea via modeling of plasma and lung pharmacokinetics coupled with the literature available regarding QSP and pharmacodynamic modeling, which integrate the viral load time-course. Furthermore, a novel pharmaceutical concept is envisioned here. For the first time in the COVID-19 literature, we have proposed the idea of transforming current antiviral regimens into single-dose long-acting injectables. By reformulating antivirals into Drug-combination Nanoparticles, the new treatment has the potential to replace 5-7 days' worth of pills or infusions. A rendering of LA remdesivir has the potential as a “flu-shot-like” injectable product to cover or treat patients for a 5-days or one-week treatment, possibly without the need for hospitalization.

Given the rapid, massive, and evolving information reported over the past months, it is important to implement systems thinking to develop and optimize therapeutic strategies that could overcome the social distancing necessary to flatten the curve of viral transmission and halt death in our communities. We have presented in this text the accumulated knowledge about virology, host-virus interaction time course, and disease progression in the context of Systems Pharmacology and modeling analysis. This manuscript advises the use of QSP and PBPK modeling to guide the choice and use of repositioned therapeutic agents, either alone or in combination. Overall, Systems Pharmacology thinking using state-of-the-art computational and long-acting methods can significantly contribute to the treatment of COVID-19 and it can represent an invaluable asset to combat future pandemics.

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