Abstract
Repurposing of remdesivir and other drugs with potential antiviral activity has been the basis of numerous clinical trials aimed at SARS-CoV-2 infection in adults. However, expeditiously designed trials without careful consideration of dose rationale have often resulted in treatment failure and toxicity in the target patient population, which includes not only adults but also children. Here we show how paediatric regimens can be identified using pharmacokinetic-pharmacodynamic (PKPD) principles to establish the target exposure and evaluate the implications of dose selection for early and late intervention. Using in vitro data describing the antiviral activity and published pharmacokinetic data for the agents of interest, we apply a model-based approach to assess the exposure range required for adequate viral clearance and eradication. Pharmacokinetic parameter estimates were subsequently used with clinical trial simulations to characterise the probability target attainment (PTA) associated with enhanced antiviral activity in the lungs. Our analysis shows that neither remdesivir, nor anti-malarial drugs can achieve the desirable target exposure range based on a mg/kg dosing regimen, due to a limited safety margin and high concentrations needed to ensure the required PTA. To date, there has been limited focus on suitable interventions for children affected by COVID-19. Most clinical trials have defined doses selection criteria empirically, without thorough evaluation of the PTA. The current results illustrate how model-based approaches can be used for the integration of clinical and nonclinical data, providing a robust framework for assessing the probability of pharmacological success and consequently the dose rationale for antiviral drugs for the treatment of SARS-CoV-2 infection in children.
Highlights
The global spread of the SARS-CoV-2 virus has impelled clinical drug developers, and academic investigators worldwide to explore the efficacy of novel candidates and existing medicinal products with antiviral and anti-inflammatory properties for the treatment of coronavirus disease 2019 (COVID-19)
Our objectives were three-fold (1) to illustrate how population pharmacokinetic modelling and extrapolation can be used in conjunction with clinical trial simulations to describe the systemic and putative target tissue exposure in a paediatric population receiving three drugs previously proposed for the treatment of adult COVID-19 patients with mild and moderate symptoms, namely CQ and HCQ and RDV; (2) to assess the probability target attainment (PTA) following different doses and dosing regimens; and (3) to compare simulated plasma levels to reported safety thresholds to support go/no-go decision to proceed with the implementation of a clinical trial
Predicted pharmacokinetic profiles and systemic concentrations for CQ and HCQ were in agreement with previously published data following administration of both drugs to paediatric patients at a dose range comparable to that included in the simulation scenarios
Summary
The global spread of the SARS-CoV-2 virus has impelled clinical drug developers, and academic investigators worldwide to explore the efficacy of novel candidates and existing medicinal products with antiviral and anti-inflammatory properties for the treatment of coronavirus disease 2019 (COVID-19). Pharmaceutics 2021, 13, 1299 for translation, integration, and extrapolation of pharmacokinetic and pharmacodynamic data [1,2] Such a scientific rift has resulted in randomised controlled and observational clinical trials of questionable scientific quality, including interventions that had poor dose rationale. Variant strains of SARS-CoV-2 have since appeared, having higher infectivity rates and posing a greater risk to children This increases the chances of progression and clinical presentation, from mild symptoms to severe inflammatory syndrome [6,7], in children with underlying health conditions. Among these, it is worth mentioning immunodeficiencies, agammaglobulinemia, Bruton’s disease, Wiskott-Aldrich syndrome, cystic fibrosis as well as those undergoing therapy for haemato-oncology. Another vulnerable group includes preterm new-borns with associated pulmonary fibrosis or dysplasia [8]
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