Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective

Abstract

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.

Keywords: COVID-19; Long-acting; Modeling; Pharmacokinetics; SARS-CoV-2; Systems pharmacology.

Fig. 1

Schematic representation about SARS-CoV-2: (a) viral structure and mode of infection, (b) immune response and proinflammatory pathways, (c) replication cycle in host cells leading to (d) multiple organ failure in late-stage infection. Panel a: The structure of the SARS-CoV-2 virus consists of a membrane made up of membrane proteins M, envelope E, and protruding spike proteins S. Inside the viral particle the long viral single-strain RNA is associated with nucleocapsids N. Upper airways are exposed to viral particles, which subsequently invade the respiratory epithelium in both the upper and lower respiratory tracts. The virus attacks the host by attaching via the viral spike glycoprotein (S) to bind to host membrane receptors ACE2. Panel b: The lung epithelium and resident monocytes trigger an innate immune response when viral RNA activates cellular pattern recognition receptors (PRR). This causes the secretion of several different cytokines and chemokines such as interferons (IFN) and interleukins (IL) to induce an immune response. Dysregulation of proinflammatory processes by the virus can lead to a cytokine storm where hyper-inflammation could lead to severe tissue damage and cell lysis. Pharmacological opportunities to normalize the immune response causing the cytokine storm are under evaluation, including IL-blockers and corticosteroids. Panel c: Viral replication occurs mostly in the cytoplasm of lung epithelia. The virus initially infects cells by entering via membrane fusion or endocytosis. The viral genome is released and undergoes translation processes to produce viral structural and non-structural proteins. Important viral proteins in the lifecycle are proteases and polymerases. These proteins allow for viral replication to develop mature virions. The virions exit the host cell by exocytosis and cellular lysis. Progeny is released to infect other cells. Several existing FDA-approved antiviral drugs are repositioned to inhibit different steps of the lifecycle, from entry/fusion (e.g., hydroxychloroquine) to inhibiting proteases (e.g., lopinavir), or inhibiting the polymerase (e.g., remdesivir). Interferons (IFN) and chloroquine may have double antiviral and immunomodulatory effects. Panel d: In addition to local lung damage, in advanced patients, other distant organs such as the kidney, liver, and gastrointestinal tract may suffer from failure or exacerbate preexisting conditions to failure.

Fig. 2

Time-course of SARS-CoV-2 infection with viral load, pathology, host response, and ensuing potential for seroconversion. Infection timeline based on data collected via AI-based searches on the most relevant/impactful literature (as of September 2020). Upper panel (Pathology): After a SARS-CoV-2 infective exposure, 57% of the subjects exhibit COVID-19 mild symptoms on day 5 (dry cough, fever, myalgia, etc.), while the remainder 43% remain asymptomatic (yet contagious). Of those displaying symptoms, 19% may progress to severity (pneumonia, cytokine storm), out of which 35% may further exacerbate into critical conditions, requiring respiratory aid. Mid-panel (SARS-CoV-2 Dynamics): Owing to current RT-PCR assay quality and swab collection methods, the viral load might be undetectable up until a few days later from symptoms onset. The viral load may peak at around day 10 to then lower in healing patients, or stay high in complicated subjects at the disease “turning point” at about 2 weeks. At peak, seroconversion likely occurs. IgM and then IgG start appearing in the blood at around 3 weeks and likely plateau at 4 weeks. In critically or severely ill patients' seroconversion might be delayed and the titer is unclear with time. Lower Panel (Pharmacological Treatments): Drugs and therapies can be broadly divided into those that aim to curb viral replication (antiviral effects) advised to be given at early stages of infection to flat the viral curve, and those that aim to modulate host response (immune-modulatory effects) advised as a cytokine storm remedy for severely ill patients.

Fig. 3

COVID-19 clinical trials registered in www.clinicaltrials.gov including drugs (alone or in combination) that are discussed in this paper and divided by effects elicited. Count of all the registered clinical studies about COVID-19 (all status, www.clinicaltrials.gov, accessed Sep 2020), that are discussed or mentioned in the text, or reported in Table 1. Panel a: The proportion of repositioned antivirals is 45%, while those repositioned as immunomodulatory compounds are 30%. The remaining 30% of clinical trials contain agents pharmacologically not well-defined and therefore denoted by “other” (e.g., vitamins, oxygen therapy, stem cells, etc.). Panel b: Percentage of clinical studies about antiviral drugs that we cover in the text and report in Table 1. We discuss/mention 74% of the total antivirals clinically tested. Panel c: Percentage of clinical studies about immunomodulatory drugs that we cover in the text and report in Table 1. We discuss 47% of the total immunomodulators clinically tested.

Fig. 4

Graphical presentation of the impact of transforming lopinavir and remdesivir into long-acting injectables based on a platform technology called Drug-combination Nanoparticle (DcNP) developed for HIV drug combination therapy; DcNP projections are derived from QSP-based simulation using a validated MBPK model and extrapolations to humans. Current experimental COVID-19 treatments for lopinavir and remdesivir call for a min of 7 and 5 days, respectively. Concentration-times in the plasma of lopinavir and remdesivir are depicted either as standard formulations (dashed lines with clinical data marked as “x”) or conceptualized in Drug-combination Nanoparticles (DcNP, bold solid lines), vs. reported in vitro concentration of a drug that gives a half-maximal response (EC₅₀, dot lines). Panel a: comparison of a week of therapy with lopinavir-ritonavir, either as standard oral dosage (free, dashes with x marks) or formulated into DcNP (solid lines). In the oral free therapy, COVID-19 individuals are dosed with two loading doses (Table 2, 800-200mg, longer arrows), followed by standard Kaletra treatment (400:100 mg, smaller arrows) twice a day for the remaining 6 days (displaying non-linear pharmacokinetics). When DcNP-lopinavir (long-acting) plasma concentration-time is simulated via an HIV MBPK model a single-dose subcutaneous administration (800:200mg lopinavir-ritonavir, full arrow) could potentially provide an extended above-or-equal EC₅₀ plasma level for the entire week. Panel b: comparison of 5-days therapy with remdesivir, either as standard IV infusion (free, dashes with x marks in the first dose, dashes only in the following administrations) or formulated into DcNP (solid lines). In the free IV therapy, COVID-19 individuals are dosed with one loading dose (Table 2, 400 mg, longer arrow), followed by standard IV treatment (200mg, smaller arrows) once a day for the remaining 4 days. When DcNP-remdesivir (long-acting) plasma concentration-time is simulated via an HIV MBPK model a single-dose intravenous administration (7 mg remdesivir, full arrow) could potentially provide an extended above-EC₅₀ plasma level for the entire 5-days period.