A call for the appropriate application of clinical pharmacological principles in the search for safe and efficacious COVID‐19 (SARS‐COV‐2) treatments

Abstract

The rapid emergence of coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to remarkable efforts by the scientific communities internationally to identify potential pharmacological treatments through the rapid initiation of clinical trials of novel and/or re-purposed regulatory authority-approved therapies. We greatly welcome the significant global effort to safely expedite trials. However, we are concerned that many studies have not been of high quality to generate clinically meaningful data to enable effective translation to clinical practice. Identifying the “right” drug (or drug combinations) is only the first step. Applying core clinical pharmacology principles at all stages of research will help identify the right dose, the right patient, and the right treatment protocol. We hope that by setting out the principles outlined in this statement, efforts to find a safe and efficacious treatment for COVID-19 will have the best chance of success. At the time of writing (dated 20/5/2020), over 1,000 clinical trials are underway for the successful treatment of COVID-19 infections, with most trials testing remdesivir, hydroxychloroquine, lopinavir/ritonavir and azithromycin separately or in combination. Drug development to treat COVID-19 has mainly focused on antivirals and immune modulators, with the logic that the early stages of the disease are characterised by the viral infection/replication stage, whereas the later, severe stage is characterised by the so-called ‘cytokine storm’. The later phase is experienced by a subset of patients but is the major cause of fatalities. The enthusiasm for antiviral agents has been driven by the successful demonstration of in vitro antiviral efficacy using cell culture experiments, often without concomitant studies in appropriate pre-clinical species and at doses that may be unsafe or unachievable in humans. Further, in vitro efficacy does not guarantee that a drug will be efficacious and safe in humans using doses required to achieve free drug concentrations at the sites of infection, even for those agents already marketed for other indications. The repurposing and trialling of immune modulatory agents, such as those targeting IL6, TNF-α, IL1 and JAK, is because over-production of pro-inflammatory cytokines has been implicated in tissue injury (especially in the lungs), leading to multi-organ failure and death. However, at this stage of the disease, we cannot exclude that the virus itself is also responsible, either partly or wholly, for the organ manifestations observed in COVID-19. It is therefore important that treatment choice must be connected to understanding of disease mechanism. An understanding and application of the core principles of clinical pharmacology can help researchers navigate the known challenges of drug discovery and development. These principles are vital to support medication choice, clinical trial design, dose selection and dose individualisation, relative to the stage of viral infection. In this statement, we outline five core principles (Figure 1) to ensure safety and efficacy of proposed treatments, some of which are relevant to antiviral drug development only (principles 1 and 3), while others apply to both antivirals and immune modulators (principles 2, 4 and 5). The aim of this statement is to provide benchmark recommendations for those publishing results, reporting results or developing clinical trials for the treatment of COVID-19. This is essential to understand the public health impact of potential COVID-19 treatments. The drug demonstrates activity against the target virus in pre-clinical studies at doses shown or predicted to be tolerated by humans. The optimal concentrations of antiviral and immunomodulatory drugs can be achieved for the proposed therapy in the relevant compartment(s) (plasma, cells and tissues). Quantification of in vivo viral dynamics and time course should be undertaken concurrently (Figure 1). Demonstrate posology optimisation for antiviral and immunomodulatory drugs to ensure the appropriate intensity and timing of therapy. Robustly designed and innovative (e.g. adaptive) randomised controlled trials should be used to determine efficacy and safety so that the benefit-harm balance of treatments are identified, rather than treatments being made solely available through compassionate use programmes. A number of potential therapies are emerging (e.g. anticoagulants, fibrinolytic agent, and agents that work on the renin angiotensin system) as our understanding of the pathophysiology of COVID-19 and the host response expands. The principles of rigorous scientific assessment described above apply equally to these potential therapies. COVID-19 is having such an enormous impact on individuals, populations, and on the economy. There is urgent need to develop safe and efficacious treatments that can reduce morbidity and mortality, and restore societal norms. However, this should not come at the expense of the quality of science and clinical medicine. In many instances, the adoption of un-trialled and potentially dangerous treatments (and combinations) has dominated the discourse and caused patient harm. To better understand the scope of potential therapies, we advocate that these five key clinical pharmacological principles should be adopted by the scientific and clinical communities to improve the development of safe and efficacious treatments for SARS-CoV-2. There are no competing interests to declare. Vice President, APFP, Professor Alastair Stewart, ARC Centre for personalised Therapeutics Technologies, University of Melbourne. Melbourne, Australia Former President, CNPHARS, Professor Guanhua Du, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. Beijing 100050, China Chairperson, EACPT, Professor Jamie Coleman MBChB, MA (Med Ed), MD, FCRP (UK), FBPhS, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham. B15 2TT, UK President, FPM, Professor Tim Higenbottam DSc MA MD FRCP PFPM, 19 Angel Gate, 326a City Road, London, EC1V 2PT, UK President, IUPHAR, Professor Ingolf Cascorbi, Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Arnold-Heller-Str. 3, D-24105 Kiel, Germany President, JPS, Kazuhiko Yanai MD PhD, Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan President, JSCPT, Kazutaka Shimoda MD PhD, Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Shimotuga, Tochigi, 321-0293, Japan

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