Background The broad-spectrum antiparasitic drug ivermectin is widely used in children, and its use in children weighing < 15 kg is off-label, as little data is available to inform the use of ivermectin in this young age group. Pediatric doses associated with consistent exposure across age are still unknown. Therefore, we aim to identify a dosing strategy for ivermectin treatment in both pre-school-aged children (2–5 years of age) and school-aged children (6–12 years of age) that achieves equivalent exposure coverage in children and adults.

Methods A population pharmacokinetic model for ivermectin was developed based on data collected in 80 pre-school-aged children (2–5 years), 120 school-aged children (6–12 years),¹ and eleven adults,² receiving an oral dose of 100–600 µg/kg ivermectin. Model-based simulations were performed to optimize pediatric dosing to achieve consistent exposure across various age groups.

Results Clearance per kilogram was higher in children than in adults, with a median (90% confidence interval) of 0.35 (0.12–0.73) L/h/kg in children compared to 0.20 (0.10–0.31) L/h/kg in adults. As a result, ivermectin exposure in children following a 200 µg/kg dose is ∼30% lower than in adults. An increased dose of 250 and 300 µg/kg would be needed in school-aged children (6–12 years) and pre-school-aged children (2–5 years), respectively, to achieve equivalent exposure coverage in children and adults. Alternatively, we propose a height-based dosing schedule with a stepwise increase in number of administered 3-mg-tablets from 1 to 5 for children in sub-Saharan Africa with a height of 75–90 cm, 90–130 cm, 130–150 cm, 150–165 cm, and 165–175 cm.

Conclusion We report the first dosing strategy for the widely-used drug ivermectin that is associated with equivalent exposure coverage in children and adults. Further studies are necessary to establish the safety and efficacy of appropriate doses in the pediatric population.

References

1. Wimmersberger D, Coulibaly JT, Schulz JD, Puchkow M, Huwyler J, N´Gbesso Y, et al. Efficacy and Safety of Ivermectin Against Trichuris trichiura in Preschool-aged and School-aged Children: A Randomized Controlled Dose-finding Trial. Clin Infect Dis 2018; 67(8):1247–55.

2. Schulz JD, Neodo A, Coulibaly JT, Keiser J. Development and validation of a LC-MS/MS method for ivermectin quantification in dried blood spots: application to a pharmacokinetic study in Trichuris trichiura-infected adults. Anal. Methods, 2018, 10, 2901–9.

Disclosure(s) JMB declares no potential conflicts of interest. JDS declares no potential conflicts of interest. JTC declares no potential conflicts of interest. JK was financially supported by the Bill and Melinda Gates Foundation (OPP1153928) and an ERC grant (CoG 614739 A-HERO), and declares no other potential conflicts of interest. MP has a part-time employment with the consulting company Certara LP (USA), and declares no other potential conflicts of interest.