Pharmacometrics to Evaluate Dosing of the Patient-Friendly Ivermectin CHILD-IVITAB in Children ≥ 15 kg and <15 kg

Abstract

The antiparasitic drug ivermectin is approved for persons > 15 kg in the US and EU. A pharmacometric (PMX) population model with clinical PK data was developed (i) to characterize the effect of the patient-friendly ivermectin formulation CHILD-IVITAB on the absorption process and (ii) to evaluate dosing for studies in children < 15 kg. Simulations were performed to identify dosing with CHILD-IVITAB associated with similar exposure coverage in children ≥ 15 kg and < 15 kg as observed in adults receiving the reference formulation STROMECTOL^®. A total of 448 ivermectin concentrations were available from 16 healthy adults. The absorption rate constant was 2.41 h⁻¹ (CV 19%) for CHILD-IVITAB vs. 1.56 h⁻¹ (CV 43%) for STROMECTOL^®. Simulations indicated that 250 µg/kg of CHILD-IVITAB is associated with exposure coverage in children < 15 kg consistent with that observed in children ≥ 15 kg and adults receiving 200 µg/kg of STROMECTOL^®. Performed analysis confirmed that CHILD-IVITAB is associated with faster and more controlled absorption than STROMECTOL^®. Simulations indicate that 250 µg/kg of CHILD-IVITAB achieves equivalent ivermectin exposure coverage in children < 15 kg as seen in children ≥ 15 kg and adults.

Introduction

Ivermectin has been a cornerstone in the treatment and control of parasitic infections since its introduction in the 1980s, providing broad-spectrum efficacy against a wide range of conditions including lymphatic filariasis, onchocerciasis, head lice, intestinal helminths, strongyloidiasis, and scabies [1]. Ivermectin is on the World Health Organization’s List of Essential Medicines, underscoring its significance in global health [2]. Approximately 400 million ivermectin treatments are distributed annually by mass drug administration (MDA) to control and eliminate onchocerciasis and lymphatic filariasis [3]. In addition, since 2023, a conventional ivermectin tablet formulation (Subvectin) has been registered in Switzerland for the treatment of scabies in adults, and high priority has been given to research on child-friendly treatment modalities [4,5]. Despite its extensive use in adults, there is a significant gap in knowledge regarding its pharmacokinetic profile in young children, particularly those with a weight of less than 15 kg. Children weighing less than 15 kg are excluded from official MDA treatment programs; thus, they do not receive the benefits of ivermectin to control numerous neglected tropical diseases (NTDs) that afflict young children [6,7,8]. Further, this contraindication leads to off-label use of ivermectin without a robust evidence base for appropriate dosing in children weighing less than 15 kg.
Traditional ivermectin tablet formulations are not suitable for children weighing less than 15 kg, necessitating innovative approaches to ensure acceptability, safety and efficacy. There is a need for new, child-friendly formulations of ivermectin that can ensure accurate dosing, improved acceptability, palatability, safety during administration, and stability suitable for diverse environmental conditions where these NTDs occur. Young children are an extremely important population suffering a disproportionate health burden from helminth and scabies infection [6]. Previous studies have highlighted significant inter-individual variability in drug exposure with STROMECTOL® [9,10], prompting a detailed comparison to ensure that new formulations can provide consistent and reliable therapeutic outcomes. Indeed, children weighing less than 15 kg that were treated with ivermectin doses less than 200 µg/kg were less likely to achieve therapeutic success for scabies compared to children treated with doses 200 µg/kg and above [11]. To address these needs, a novel orodispersible tablet (ODT) formulation of ivermectin, called CHILD-IVITAB, has been developed utilizing multifunctional template inverted particle (TIP) technology, designed to provide rapid disintegration, controlled absorption, and enhanced taste masking [12,13,14,15]. The rapid disintegration time (less than 10 s) of CHILD-IVITAB greatly improves ease of administration, virtually eliminates any choking risk, and removes need for potable water, which would facilitate use of ivermectin in children under 15 kg in MDA programs. To inform the pediatric program of CHILD-IVITAB, 16 healthy adults were enrolled in a phase I, single-center, open-label, randomized, two-period, cross-over, single-dose trial which aimed to compare the palatability, tolerability, and bioavailability and pharmacokinetics (PK) of CHILD-IVITAB compared against the marketed ivermectin tablets (STROMECTOL®) at a single dose of 12 mg in a fasting state. Non-compartmental analysis (NCA) demonstrated that CHILD-IVITAB yielded controlled absorption associated with reduced variability in drug exposure as compared to STROMECTOL® [16]. The objective of the present study is to develop a population PK model to characterize the absorption profile and variability of the ivermectin CHILD-IVITAB formulation compared to the reference formulation STROMECTOL®. In addition, the developed model will be applied to simulate and evaluate dosing for a planned pediatric study in children ≥ 15 kg and those < 15 kg. By addressing these aspects, the goal is to contribute to optimizing ivermectin dosing strategies for children, ensuring consistent exposure and effective treatment outcomes across different age groups [7].

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The authors thank Galvita AG for the right to use their proprietary TIP technology, which was needed to produce the study medication CHILD-IVITAB.

Golhen, K.; Buettcher, M.; Huwyler, J.; van den Anker, J.; Gotta, V.; Dao, K.; Rothuizen, L.E.; Kobylinski, K.; Pfister, M. Pharmacometrics to Evaluate Dosing of the Patient-Friendly Ivermectin CHILD-IVITAB in Children ≥ 15 kg and <15 kg. Pharmaceutics 2024, 16, 1186. https://doi.org/10.3390/pharmaceutics16091186

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