Mixing of Tecovirimat in Water to Support Oral Dosing of Infants and Children With Mpox

Abstract

We demonstrated the 200 mg tecovirimat capsule can be dispersed in 20 mL of water and swirled for 30 or 60 seconds to consistently yield a 10 mg/mL suspension. This finding supports simplified alternative oral dosing of tecovirimat in younger children with mpox.

Following the 2022 mpox outbreak, dozens of cases occurred in young children within the United States, and thousands have occurred internationally, where the Clade I virus has disproportionately affected young children in the Democratic Republic of Congo and surrounding areas.¹ This is of particular concern as increased severity of disease, mortality, and rates of hospitalization have been reported in this population. Given these poor outcomes, there is a critical need for therapies in pediatric-friendly formulations.

Tecovirimat is an oral antiviral medication that is available for mpox and other non-variola orthopoxviruses under an expanded access investigational new drug protocol (EA-IND) held by the Centers for Disease Control and Prevention (CDC).² Tecovirimat is currently only available in intravenous and capsule form, which provides a challenge for children weighing less than 13 kg who may require partial oral doses of less than 200 mg. Data are available to support the mixing of capsules in either liquid (eg, 2% milk, chocolate milk, infant formula) or soft food (eg, apple sauce, yogurt) as tecovirimat is poorly water soluble.³ However, these dosing recommendations are restricted to children weighing 13 kg or more, and for those weighing less than 13 kg, there are currently no U.S. Food and Drug Administration-approved dosing recommendations. The CDC EA-IND and the dosing under evaluation in the A5418/Study of Tecovirimat for MPox (STOMP) study advise mixing of the 200 mg capsule contents in water and administering a partial dose based on the child’s weight (Figure 1).^2,4 However, there are no published data supporting this approach. Here, we evaluated the dose accuracy and recovery of tecovirimat capsule contents when mixed in water.

Figure 1.

Guidelines for mixing tecovirimat capsule contents in water.²

The capsules for this study were donated by SIGA Technologies, Inc. (Corvallis, OR). Each capsule was weighed and carefully opened over an empty 80 mL urine specimen cup, 20 mL of MilliQ water was then added, and the sides of the cup were flushed to ensure all powder was covered. The samples were then gently swirled for 30 or 60 seconds on a flat surface, and a total of 6 aliquots were drawn following gentle swirling between each aliquot and further prepared for high performance liquid chromatography (HPLC) analysis (Supplementary Methods). The percent sample recovery was calculated as the area counts for each replicate relative to the working standards assuming a nominal target concentration of 10 mg/mL, and then summarized as the average and relative standard deviation for each swirling duration. A recovery rate within ± 5% of the nominal concentration was deemed acceptable.

The average percent recovery was 99.1% (relative standard deviation [RSD] 1.8%) and 101.9% (RSD 1.0%) after 30 or 60 seconds of swirling, respectively (SupplementaryFigure S1). The slightly increased precision with the extended swirling time may be due in part to the settling rate of the suspension and the lack of viscosity of water. Both swirling times yielded concentrations within 5% of the nominal concentration for all preparations.

The ability to mix tecovirimat in a small volume of water is critical towards ensuring the appropriate dose is being administered in infants and young children weighing less than 13 kg. Previous data were limited to mixtures of 200 mg in 30 mL liquid, which would yield a 6.7 mg/mL suspension and thus require larger volumes to administer an equivalent dose.³ Furthermore, whether partial doses less than 200 mg could be reproducibly drawn up from a liquid mixture had not been established. Our findings have addressed this gap. However, these results were generated in a laboratory setting, and thus special care should be taken to closely follow instructions, particularly the need to immediately draw up the suspension following swirling before the powder has had time to settle. MilliQ water, which is purified and deionized, was also used to avoid impurities for the HPLC analysis, whereas tap water is used in clinical practice. Differences between these water types are not anticipated. A powder for reconstitution formulation is in development by SIGA Technologies, which will help overcome the current challenges with the capsule formulation.

The currently recommended tecovirimat oral dosages in children weighing less than 13 kg are outlined in Figure 1. The dosing strategy outlined in Figure 1 is in use under the EA-IND and was under investigation in A5418/STOMP to ensure adequate tecovirimat exposures were achieved in younger children.^2,4 However, A5418/STOMP recently stopped enrollment due to tecovirimat not improving clinical or pain resolution in adults with clade II infection,⁵ and PALM007, which primarily enrolled children with clade I infection, also did not show improvement in clinical resolution.⁶ Further analyses are underway to inform the future use of this agent.

Our findings support the ability to mix tecovirimat capsules in water to support weight-based oral doses of tecovirimat in children weighing less than 13 kg. More broadly, these findings provide an example of a simplified approach to quickly assess alternative drug administration strategies in pediatric populations where child-friendly formulations are not readily available.

Funding

Support for the Advancing Clinical Therapeutics Globally (ACTG) Network was provided by the National Institute of Allergy and Infectious Diseases (NIAID) under award numbers UM1AI068634 (ACTG SDAC), UM1 AI068636 (ACTG LOC), and UM1 AI106701 (ACTG LC). Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by NIAID with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or SIGA Technologies.

Conflicts of interest

KMB has received consulting fees from ViiV Healthcare. JJK is currently an employee of Merck. The remaining authors have nothing to declare.