Abstract
Dengue disease is an important problem in global public health. Annually, 390 people are infected with dengue virus. The majority of infections results in asymptomatic cases. For symptomatic cases, patients will develop either mild dengue fever (DF) or severe dengue hemorrhagic fever (DHF). DF is a self-limiting disease meaning the patients will recover within 4-7 days without any significant intervention. However, DHF patients will eventually develop plasma leakage which may progress into potentially fatal hypovolemic shock known as dengue shock syndrome (DSS) without prompt and adequate fluid management. Dengue disease is caused by dengue virus which belongs to the genus Flavivirus. There are four serotypes of the virus including dengue virus 1, 2, 3 and 4. The virus is transmitted by Aedes mosquitoes. There is no antiviral drug against dengue virus and the only available vaccine has limited efficacy and elevates the risk of hospitalization from dengue disease in seronegative vaccines. We previously conducted a phase 2/3 trial by repurposing ivermectin to treat adult dengue patients. We found that ivermectin was safe, and the drug could significantly speed dengue virus non-structural protein NS1 clearance. In addition, the drug showed a potential efficacy in reducing the severity of the disease. In this study, we primarily evaluated the safety and pharmacology of ivermectin in pediatric dengue patients (age younger than 15 years and weighing more than 15 kilograms). Since ivermectin ingestibility, absorption, metabolism and excretion in pediatric patients were expected to be dissimilar from adult patients, this study was essential for determining the appropriate dose of ivermectin before conducting a trial for evaluating clinical efficacy. Two doses of ivermectin were studied: 400 μg/kg per day for three days and 600 μg/kg per day for three days. The patients in each dosage group were also stratified by weights into two groups including those weighing over 30 kg and those weighing between 15 to 30 kg. Our analyses showed that both doses of ivermectin were safe for treating pediatric dengue patients. However, no dose dependent relationship in efficacy against viral load or NS1 levels were found between the two administered doses. Advanced pharmacological analysis is required to confirm this finding. If the finding is confirmed, the more appropriate dose for phase 3 clinical trials in pediatric patients will be 400 μg/kg per day for three days.
