Silvia Grandoni (1,2) , Sean Oosterholt (2), Oscar Della Pasqua (1,2,3)
(1) Consiglio Nazionale Delle Ricerche (CNR), Rome, Italy (2) Clinical Pharmacology & Therapeutics Group, University College London, London, UK (3) Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Brentford, UK
Introduction: At the beginning of the COVID-19 pandemics, it seemed that infected children were asymptomatic, or likely to develop only mild symptoms. Today, it is known that a small proportion of paediatric patients infected by SARS-CoV-2 virus progresses to a condition defined by WHO as Multisystem Inflammatory Syndrome in Children (MIS-C), which requires hospitalization and intensive care [1]. Thus far treatment protocols have been based on symptom management with treatment based on similar conditions such as Kawasaki disease, or COVID-19 in adults [1]. As high levels of inflammatory biological markers such as IL-6 and C-reactive protein (CRP) have been observed as in adults [1-3], the use of anti-IL-6 drugs has been proposed as first line therapy. Similarly, haemoadsorption therapy has been suggested as adjuvant at the start of treatment to control the inflammatory response and improve lung function. Despite numerous investigations in adults, the relevance of IL-6 inhibitors for the treatment of MIS-C along with the rationale for the paediatric dose have been poorly investigated.
Objectives: Here, we illustrate the implementation of a model-based approach for the evaluation of the anti-inflammatory activity of IL-6 inhibitors as first line therapy for early intervention in COVID-19 MIS-C patients at risk of disease progression. Treatment effect was evaluated in conjunction with hemoperfusion (HP) as an alternative intervention for rescuing patients with clinically important increase in circulating levels of IL-6. Given its mechanism of action, siltuximab (SIL) was used as a case study drug for possible evaluation in a paediatric clinical trial.
Methods: Clinical trial simulations (CTS) were implemented using an adapted population pharmacokinetic-pharmacodynamic (PK-PD) model previously developed for the evaluation of CRP response in Castleman’s disease patients [4]. Model adaptations included variable CRP production rate and the effect of body weight on disposition parameters. The contribution of HP was evaluated considering the effect of the removal of circulating IL-6 and decreased CRP production rate following two 4-h sessions of HP. Simulation scenarios were explored to assess the proportion of adult COVID-19 and MIS-C patients that reaches CRP levels value of 10 mg/L, as well as the time required to achieve this threshold [5].
Assumptions: Whilst the initial model parameterisation was based on a chronic inflammatory disease, assumptions have been made regarding IL-6 and CRP formation rates to account for the acute inflammatory response associated with MIS-C. In addition, shortening of the duration of the exposure to high levels of circulating IL-6 and CRP was assumed to be prognostic of overall clinical improvement [5]. These assumptions are based on the evidence that 1) CRP is the principal downstream mediator of the acute-phase response following an inflammatory event; 2) even though IL-6 is necessary for CRP gene induction, it is not sufficient to achieve this alone and 3) CRP can activate the complement pathway and initiate cell-mediated pathways by binding to Fc receptors, leading to the release of pro-inflammatory cytokines.
Virtual patients population: Children older than 1 year of age were considered for the purpose of this analysis. In addition to the effect of body weight, variable baseline serum CRP (50, 100 and 200 mg/L) were considered [2,9], [6-8].
Results: In adults, following SIL monotherapy, it can take up to about four days for CRP levels to get back to the normal range. Similar results were observed for the paediatric population, as baseline CRP levels are as high as in adults. At the approved dosage, the maximum proportion of patients with CRP levels <10 mg/L is about 70% for patients showing low elevation at the start of treatment. This proportion is reduced up to about 35% if baseline CRP levels are >200 mg/L. A slight improvement in the CRP profiles can be seen in the multimodal treatment scenario.
Conclusions: This analysis suggests limited immediate benefit of SIL for the treatment of severe COVID-19 and MIS-C patients without HP. The delay in reducing CRP-related inflammatory response can have deleterious effect on critical organs, despite the overall decrease in CRP levels at a later time. Any benefits from a multimodal treatment are likely to be caused by removal of interleukin-1β (IL-1β), tumour necrosis factor-α (TNFα), and other pro-apoptotic cytokines induced by CRP.
References:
[1] L. Jiang et al., “COVID-19 and multisystem inflammatory syndrome in children and adolescents”, Lancet Infect. Dis.,(2020)
[2] C. R. Consiglio et al., “The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19”, Cell (2020)
[3] A. H. Rowley, “Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children” , Nat. Rev. Immunol. (2020)
[4] C. L. Mayer, L. Xie, and R. Bandekar, “Dose selection of siltuximab for multicentric Castleman ’ s disease”, Cancer Chemother. Pharmacol. (2015)
[5] R. N. Sproston and J. J. Ashworth, “Role of C-reactive protein at sites of inflammation and infection”, Front. Immunol. (2018)
[6] J. H. Stone et al., “Efficacy of Tocilizumab in Patients Hospitalized with Covid-19,” N. Engl. J. Med. (2020)
[7] O. Hermine et al., “Effect of Tocilizumab vs Usual Care in Adults Hospitalized with COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial,” JAMA Intern. Med. (2021)
[8] V. C. Veiga et al., “Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: Randomised controlled trial”, BMJ (2021)
[9] L. R. Feldstein et al., “Multisystem Inflammatory Syndrome in U.S. Children and Adolescents”, N. Engl. J. Med. (2020)
[10] T. Rampino et. al, “Hemoperfusion with CytoSorb as Adjuvant Therapy in Critically Ill Patients with SARS-CoV2 Pneumonia”, Blood Pur (2020)
Reference: PAGE 29 (2021) Abstr 9835 [www.page-meeting.org/?abstract=9835]
Poster: Drug/Disease Modelling - COVID-19