Novel Patient-Friendly Orodispersible Formulation of Ivermectin is Associated With Enhanced Palatability, Controlled Absorption, and Less Variability: High Potential for Pediatric Use

Abstract

Ivermectin has been used since the 1980s as an anthelmintic and antiectoparasite agent worldwide. Currently, the only available oral formulation is tablets designed for adult patients. A patient-friendly orodispersible tablet formulation designed for pediatric use (CHILD-IVITAB) has been developed and is entering early phase clinical trials. To inform the pediatric program of CHILD-IVITAB, 16 healthy adults were enrolled in a phase I, single-center, open-label, randomized, 2-period, crossover, single-dose trial which aimed to compare palatability, tolerability, and bioavailability and pharmacokinetics of CHILD-IVITAB and their variability against the marketed ivermectin tablets (STROMECTOL) at a single dose of 12 mg in a fasting state. Palatability with CHILD-IVITAB was considerably enhanced as compared to STROMECTOL. Both ivermectin formulations were well tolerated and safe. Relative bioavailability of CHILD-IVITAB compared to STROMECTOL was estimated as the ratios of geometric means for Cmax,AUC 0-∞, and AUC0-last, which were 1.52 [90% CI: 1.13-2.04], 1.27 [0.99-1.62], and 1.29 [1.00-1.66], respectively. Maximum drug concentrations occurred earlier with the CHILD-IVITAB formulation, with a median Tmax at 3.0 h [range 2.0-4.0 h] versus 4.0 h [range 2.0-5.0 h] with STROMECTOL (P = .004).With CHILD-IVITAB, variability in exposure was cut in half (coefficient of variation: 37% vs 70%) compared to STROMECTOL. Consistent with a more controlled absorption process, CHILD-IVITAB was associated with reduced variability in drug exposure as compared to STROMECTOL. Together with a favorable palatability and tolerability profile, these findings motivate for further clinical studies to evaluate benefits of such a patient-friendly ODT formulation in pediatric patients with a parasitic disease, including infants and young children <15 kg

Introduction

Ivermectin has been used since the 1980s as an oral antiparasitic agent for many indications. It is effective in treating parasitic diseases such as onchocerciasis, lymphatic filariasis, strongyloidiasis, head lice, intestinal nematodes, and scabies. The burden of these diseases is high, particularly in children younger than 5 years in low- and middle-income countries (LMICs). The importance of oral ivermectin for numerous neglected tropical diseases is well  stablished, placing it on the WHO List of Essential Medicines for Children for treatment of ectoparasitic, filarial, and intestinal helminth infections. Through a national survey of clinicians of different specialties managing children with scabies in Switzerland, there was a call to give high priority to research on child-friendly treatment modalities. Currently approved and commercially available ivermectin formulations such as STROMECTOL are listed in the WHO referenced “Drug Bank Online.” Furthermore, an oral form recently authorized in Switzerland is also only available as a tablet designed for adults. In children <6 years currently available ivermectin formulations need to be  administered as crushed tablets or in a suspended form, both prone to imprecise dosing (loss of product after crushing or sedimentation of product after suspension). They are also not palatable, and thereby predisposed to be expelled out of the mouth by children.

When available, oral liquid medicinal product formulation is a common alternative to solid oral dosage forms to ease medicine administration. In Latin America, a liquid oral ivermectin formulation has been manufactured and used in trials for treatment of young children with head lice in Colombia and myiasis in Peru. Nevertheless, this liquid oral formulation has been discontinued since. In Germany, a liquid oral ivermectin formulation was developed, but not evaluated in trials. However, oral liquid formulations are suboptimal in infants and toddlers. Aside from poor palatability, ivermectin as a suspension is not viable in clinical practice as the stability is fragile, the shelf life is short (2-3 weeks), and the suspension is affected by UV light exposure. For these reasons, such formulations are not desirable for the hot and humid tropical conditions found in a majority of LMICs. All the above compromise drug adherence and effectiveness of prevention and treatment of parasitic diseases with ivermectin, particularly in young children and infants.

It should be noted that safety of ivermectin in young children <15 kg and pregnant women has not been evaluated in clinical studies so far. Owing to its high effectiveness against different diseases and lack of alternative child-friendly modalities, it is nevertheless frequently administered as crushed tablets off -label in these sensitive populations, and is prone to dosing errors associated with efficacy and safety risks. An appropriate pediatric ivermectin formulation, which can be readily used in the clinic and mass drug administration settings in LMICs, has not yet been developed nor clinically evaluated. For a child-friendly drug delivery strategy, orodispersible tablets (ODT) in the form of inorganic particulate drug carriers can be used as multifunctional excipients offering a potential solution to address unique medical needs in infants and children, while maintaining a favorable excipient safety and acceptability profile in these vulnerable patient populations.

A recent study has shown such novel orodispersible formulation, used as placebo ODT with food-grade orange aroma, to be well accepted by children. A promising drug delivery device, namely multifunctional template inverted particles (TIP) microcapsules loading an active ingredient, has been developed for ivermectin. It is expected to enable fast oral disintegration associated with rapid and controlled drug absorption and enhanced taste masking. High interindividual variability in drug exposure with STROMECTOL has been highlighted in previously published studies. Ahead of testing this novel TIP-based ivermectin mini ODT (CHILD-IVITAB) in children, a clinical study is warranted with specific interest in investigating the variability in ivermectin absorption and pharmacokinetics with CHILD-IVITAB as compared to STROMECTOL in healthy adults, in addition to evaluating its palatability and tolerability. The overall goal of this project is to develop a childfriendly ivermectin formulation for pediatric patients with a parasitic disease including infants and children <15 kg.

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Dao, K., Buettcher, M., Golhen, K., Kost, J., Schittny, A., Duthaler, U., Atkinson, A., Haefliger, D., Guidi, M., Bardinet, C., Chtioui, H., Boulekbache, A., Buclin, T., Huwyler, J., Pfister, M. and Rothuizen, L.E. (2024), Novel Patient-Friendly Orodispersible Formulation of Ivermectin is Associated With Enhanced Palatability, Controlled Absorption, and Less Variability: High Potential for Pediatric Use. J Clin Pharm. https://doi.org/10.1002/jcph.2462