Janneke M Brussee(1,2,3), Jessica D Schulz(1,2), Jean T Coulibaly(1,2,4,5), Jennifer Keiser(1,2), Marc Pfister(2,3,6)
(1) Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland. (2) University of Basel, Basel, Switzerland. (3) Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland. (4) Unité de Formation et de Recherche Biosciences, Université Félix Houphouët–Boigny, Abidjan, Côte d’Ivoire. (5) Centre Suisse de Recherches Scientifiques en Côte d’Ivoire, Abidjan, Côte d’Ivoire. (6) Certara LP, Princeton, NJ, USA.
Objectives: Soil-transmitted helminthiasis is a neglected tropical disease mostly affecting the poorest and most deprived communities in tropical and sub-tropical areas, and approximately 1.5 billion people are infected worldwide [1]. Although the broad-spectrum antiparasitic drug ivermectin is commonly used to treat various helminth infections, including soil-transmitted helminthiasis, doses associated with consistent exposure in children 2–12 years of age and adults are unknown. Ivermectin is not approved in children weighing
Methods: Ivermectin PK data was collected in 80 pre-school-aged children (2–5 years), 120 school-aged children (6–12 years) [2], and eleven adults [3] with Trichuris trichiura infections in Côte d’Ivoire following a dense sampling scheme and using the dried blood spot technique. Pre-schoolers (2–5 years) were randomized to receive 100 or 200 μg/kg, school-aged children were randomized to receive 200, 400, or 600 μg/kg, and adults received 200 μg/kg ivermectin. A population PK model was developed (NONMEM 7.4) and a systematic covariate analysis was performed to explain part of the inter-individual variability in the estimated PK parameters. The model was evaluated using goodness-of-fit plots, a bootstrap analysis (n=500), and visual predictive checks (n=1000).
Different dosing scenarios were simulated with (a) the current dose of 200 μg/kg, rounded to whole 3-mg tablets, (b) an increased weight-based dose, and (c) an increased dose based on height. Different cut-off points for body weight and height in children in scenarios (b) and (c) were evaluated, to achieve equivalent exposure coverage in children and adults, with a target exposure within the 80–125% range of the median adult exposure observed with a 200 μg/kg ivermectin dose.
Results: A two-compartmental PK model was developed to describe ivermectin PK in children and adults, and included two transit compartments to account for a delay in absorption, with a mean transit time (MTT) of 3.14 h (median, 90% confidence interval (90% CI) 1.61–6.43 h). A typical individual of 18 kg had a clearance of 5.98 L/h, and clearance was found to increase with body weight. Clearance per kilogram bodyweight in pre-school-aged children was similar to that in school-aged children with median values of 0.346 (90% CI 0.12–0.73) L/h/kg and 0.352 (0.17–0.69) L/h/kg, respectively.
In adults, clearance per kilogram bodyweight was significantly lower (0.199 (0.10–0.31) L/h/kg). Consequently, administration of 200 μg/kg ivermectin is associated with a ~30% lower exposure in children compared to adults. Simulations indicate that an increased dose of 250 and 300 μg/kg would be needed in school-aged children and pre-school-aged children, respectively, to achieve equivalent exposure coverage in children and adults. Alternatively, we also provide a height-based dosing schedule, as height is easier to measure than body weight in settings with poor infrastructure.
Conclusions: We report the first dosing strategy for the widely-used drug ivermectin that is associated with equivalent exposure coverage in children and adults. An additional study is warranted to establish the safety of the recommended higher dose in pre-school-aged children, and the efficacy of appropriate doses against helminth infections in children.
References:
[1] World Health Organization, 2018, Factsheet on Soil-Transmitted Helminthiasis. Available from https://www.who.int/en/news-room/fact-sheets/detail/soil-transmitted-helminth-infections
[2] Wimmersberger D, Coulibaly JT, Schulz JD, Puchkow M, 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
[3] 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
Reference: PAGE 28 (2019) Abstr 8888 [www.page-meeting.org/?abstract=8888]
Poster: Clinical Applications