Repeated-Dose High-Dose Ivermectin Pharmacokinetics and Safety in Children with Acute Dengue

Ivermectin has shown anti-dengue virus activity in experimental systems, and an adult dengue trial found faster clearance of circulating non-structural protein 1 (NS1) without improvement in viremia or clinical outcomes. Pediatric pharmacokinetic and safety data for repeated high-dose regimens remain limited. We characterized repeated-dose ivermectin pharmacokinetics and safety in children with acute uncomplicated dengue weighing ≥15 kg.

In this prospective, open-label, sequential dose-escalation study, children aged 1-15 years who presented within 72 h of fever onset and met the protocol laboratory-confirmation criteria for dengue received ivermectin 400 or 600 μg/kg once daily for 3 days. Noncompartmental analyses estimated exposure and peak concentrations from intensive plasma sampling. Exploratory analyses examined associations between exposure and viremia and NS1 trajectories during the first 48 h after dose 1; the study was not designed or powered to evaluate antiviral efficacy.

All 24 children completed follow-up and experienced at least one adverse event; most events were consistent with acute dengue. Six participants (25%) experienced serious adverse events consisting of grade 4 neutropenia; all participants were clinically well, required no neutropenia-specific treatment, and showed improvement at the next available assessment or follow-up. No serious adverse event was assessed as related to ivermectin. One asymptomatic grade 1 QTc-prolongation adverse event was recorded and required no intervention. Exposure increased with dose: median 0-48-h area under the concentration-time curve (AUC_last) was 1316.49 and 2129.41 ng·h/mL at 400 and 600 μg/kg, respectively, and corresponding maximum observed concentrations (C_max) were 107.50 and 165.50 ng/mL. Dose-normalized parameters showed no clear relationship with body weight. Analyses confined to the first 48 h identified no clear exposure-response association with viremia or NS1 trajectories.

In children weighing ≥15 kg with acute uncomplicated dengue, ivermectin exposure increased with administered dose, while dose-normalized AUC_last and C_max showed no clear relationship with body weight across the studied range. Pharmacokinetics and Pharmacodynamics of Ivermectin in Pediatric Dengue Patients (PKIDEN) therefore fills an important dengue-specific pediatric clinical pharmacology gap and provides repeated-dose exposure and safety reference data that may inform dose selection, exposure interpretation, and safety monitoring in future studies. The study was not designed to determine antiviral efficacy or clinical benefit.

ClinicalTrials.gov: NCT03432442; first posted February 14, 2018.