This submission belongs to the symposium “Pharmacometric approaches in malaria research”.
Background: Ivermectin is an antiparasitic drug, which has been used in human and animals for decades. Mass ivermectin treatment in livestock has been suggested as a novel malaria vector control method, as ivermectin-treated hosts are lethal to blood-feeding Anopheles mosquitoes. A long-acting ivermectin formulation using BEPO® technology has recently been developed. This novel formulation could prolong a mosquito-lethal effect covering the duration of a transmission season.
Aims: The aims of this work were (1) to characterise the population pharmacokinetic (PK) and pharmacodynamic (PD) properties of a newly developed long-acting injectable ivermectin formulation in cattle and (2) to perform translational simulations to inform first-in-human clinical study dosing.
Methods: Two PK trials were conducted in cattle in Burkina Faso (study 1: n=20, 0.6 and 1.5 mg/kg with 3 formulations; followed by study 2: n=24, 1.0 and 1.5 mg/kg with one chosen formulation from study 1). A novel long-acting ivermectin formulation was injected subcutaneously and plasma samples were collected for approximately 4 months after a single injection. Plasma samples were shipped to Thailand for drug quantification by LC-MS/MS, and for mosquito-killing evaluations through a membrane feeding assay. For the mosquito feeding experiments, plasma samples were mixed with fresh red blood cells and fed to the two main malaria vectors in Southeast Asia, Anopheles dirus and Anopheles minimus. Ivermectin and one metabolite (3”-O-demethyl ivermectin) were detectable in plasma samples. Population PKPD modelling was performed in NONMEM v7.5. A prior model (1) was utilised to describe the disposition of ivermectin, in order to characterise the absorption properties of this novel formulation (flip-flop kinetics). Body weight was implemented allometrically on all clearance and volume parameters. Mosquito mortality of the two mosquito species was modelled using an Emax model. Translational simulations were also conducted to propose dosing associated with sustained ivermectin exposure above mosquito-lethal concentrations in a prospective first-in-human clinical study. The developed PK model for ivermectin in cattle was scaled by body weight to human, and linked to a previously developed PD model in human. Inter-individual variability was uniformly set to 10%CV on all PKPD parameters in the simulations. Body weight-scaled doses used in cattle (0.5, 1, 1.5 mg/kg) were simulated and compared to standard oral dosing in human (a single oral dose of 0.4 mg/kg and 3-day daily oral dose of 0.4 mg/kg/day).
Results: Using the prior model, a three-compartment disposition model, and parallel first-order absorption (fast and slow absorption pathway) adequately described the data. The metabolite was best described by a two-compartment disposition model. An Emax model, with the sum of ivermectin and metabolite concentrations driving the effect, was successfully utilised to describe the mosquito mortality. After administration of 0.5, 1, 1.5 mg/kg ivermectin subcutaneously, translational simulations predicted sustained killing (>IC90) for an average of 9.9, 26.1, 36.6 days for Anopheles dirus; and longer than 90 days for Anopheles minimus. This is substantially longer than the mosquito killing associated with oral dosing in human volunteers.
Discussion: The developed long-lasting ivermectin injectable formulation demonstrated sustained mosquito mortality after a single injection in cattle. Translational simulations were used to inform potential dosing in a prospective first-in-human clinical study, and showed sustained mosquito mortality after a single injection.
References: 1. Wilkinson PK, Pope DG, Baylis FP. Pharmacokinetics of ivermectin administered intravenously to cattle. J Pharm Sci 1985; 74: 1105-7.