Remdesivir: Preliminary Data and Clinical Use Versus Recommended Use

Remdesivir inhibits viral replication of severe acute respiratory coronavirus 2 in vitro and has been shown to reduce time to recovery in adults with coronavirus disease 2019 (COVID-19). It is currently the only antiviral approved by the Food and Drug Administration (FDA) for the treatment of COVID-19.^1–4  Although remdesivir is being used in children with COVID-19, it is not approved for patients <12 years of age. Fortunately, if treatment with remdesivir of COVID-19 meets key assumptions, the drug may qualify for the extrapolation pathway, whereby efficacy data in adults can be used to support efficacy in children. However, safety data cannot be extrapolated; population-specific safety data are needed to support FDA labeling for pediatric use. Thus, we read with anticipation the safety data on compassionate use of remdesivir in 77 children with severe COVID-19 presented by Goldman et al⁵  in this issue of Pediatrics. Goldman et al⁵  describe low rates of adverse events, including elevated liver aminotransferase levels and anemia, similar to the safety profile seen in adults receiving remdesivir. In light of these data, we will consider whether the concept of extrapolation could be used to support efficacy of remdesivir in children with COVID-19 and the potential additional data required for FDA approval of this drug for children.

The FDA introduced the concept of extrapolation of efficacy to pediatrics in 1994,⁶  facilitating pediatric drug development by maximizing the use of adult data while minimizing exposure of children to unnecessary clinical trials.⁷  There are critical assumptions when considering full extrapolation. Importantly, if children are provided similar exposure to a therapeutic, they should have a similar response with respect to disease progression as adults. The most common examples of extrapolation are found in infectious disease, whereby disease progressions are often similar enough to consider extrapolation, and dosing of antibiotics achieving similar levels to adults at the target typically result in a similar response to therapy. Consider the case of community-acquired pneumonia, for which the disease processes are similar to adults, except for in children <30 days old (for whom extrapolation should not be considered) as different organisms cause disease. Although the overall fraction of children with pneumonia who suffer mortality is less, the relative benefits of antibiotics in children and adults are similar. Thus, if the assumptions of extrapolation are satisfied, pediatric-specific pharmacokinetic data to identify the appropriate dosage and safety data at that dose of the drug are needed to support drug product labeling under the full extrapolation pathway. In addition to product labeling, these concepts (ensuring similar disease, similar exposure, and safety) are critically important for bedside management when using therapeutics for which data are mostly derived from adults.

We are still early in the pandemic; thus, reasonable people can disagree as to whether (or how much) we should extrapolate. Although morbidity and mortality rates differ, children hospitalized with acute COVID-19 often have a similar disease course as adults. Like adults, children suffer from pulmonary disease due to severe acute respiratory coronavirus 2 invasion of respiratory epithelia and subsequent local and systemic inflammatory responses.⁸  Similar to hospitalized adults, 1 in 3 hospitalized children requires admission to the ICU.⁹  Children with severe COVID-19 can have pulmonary infiltrates and respiratory insufficiency and failure and may require extracorporeal membrane oxygenation.⁹  Children are also likely to have a similar response to remdesivir as adults. Remdesivir inhibits RNA-dependent RNA polymerase, halting viral synthesis and replication.¹⁰  This effect is not known to be age dependent. It remains to be seen whether we can reliably extrapolate for COVID-19 with respect to therapeutics, but several key elements are in place.

The next steps toward pediatric labeling are to identify the most appropriate dose in the pediatric population and ensure safety at that dose. Ideally, pediatric dosing should achieve target organ concentrations that are comparable to those that are efficacious in adults. We recently used physiologically based pharmacokinetic modeling based on the current recommended dosing in children <40 kg (5 mg/kg administered intravenously for the initial dose, followed by 2.5 mg/kg administered intravenously for remaining doses) to simulate plasma exposures for remdesivir in pediatric patients.¹¹  This dosing strategy resulted in predicted values that were 147% to 256% of adult values. Thus, we suspect current dosing regimens used in children will provide exposures at least similar to if not higher than in adults. Clinical trials are currently ongoing to confirm these exposures in children.¹² 

Safety data such as that presented by Goldman et al⁵  are critical to support labeling of remdesivir in children. We will need additional such data, including exposure (dosing) and safety from well-conducted pharmacokinetic and safety trials. Ideally, we will eventually have outcome data relating dosing to both safety and clinical outcomes. In the meantime, we will inform families that the therapeutic benefit of remdesivir in our youngest patients is unknown as we continue research that increases our knowledge of the molecule.

COVID-19

coronavirus disease 2019

FDA

Food and Drug Administration