Oral ivermectin population pharmacokinetics modeling in venous plasma in healthy study participants in Kenya in preparation of BOHEMIA cluster randomized controlled trial
Charlotte Kern (1, 2), Yvonne Kamau (3), Kelly Ominde (3), Mercy Tuwei (3), Lawrence Babu (3), Jonathan Karisa (3), Jane Adetifa (3), Urs Duthaler (7, 8), Carlos Chaccour (4, 5, 6), Marta Maia (3,9) and Felix Hammann (1)
(1) Division of Clinical Pharmacology & Toxicology, Department of Internal Medicine, University Hospital Bern, Switzerland (2) Graduate School for Health Sciences, University of Bern, Switzerland (3) Kenya Medical Research Institute (KEMRI) Centre for Geographic and Medical Research, Kenya (4) Department of Microbiology and Infectious Diseases, Clinica Universidad de Navarra, Pamplona, Spain (5) Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Madrid, Spain (6) ISGlobal, Hospital Clinic, University of Barcelona, Spain (7) Division of Clinical Pharmacology & Toxicology, Department of Biomedicine, University and University Hospital Basel, Switzerland (8) Division of Clinical Pharmacology & Toxicology, Department of Pharmaceutical Sciences, University of Basel, Switzerland (9) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, UK
Introduction: Malaria remains a significant global public health problem although this infectious disease is preventable and treatable. Despite the large-scale implementation of preventive strategies such as bed nets or indoor insecticide spraying, the worldwide decline in malaria incidence is stalling, particularly in sub-Saharan Africa. Emerging resistance of mosquitos to insecticides and parasite resistance to drugs pose a threat to malaria elimination. Sustained control and elimination is unlikely to be achievable unless new ways of controlling the disease and its vector are developed. A promising new strategy in malaria prevention is vector control through mass drug administration (MDA) of ivermectin (1). Ivermectin’s mode of action is independent of vector behavior or insecticide resistance and therefore has the potential to directly address malaria residual transmission.
Objectives: The BOHEMIA trial aims to evaluate efficacy of ivermectin MDAs in malaria control in two study sites in Eastern Africa (2). Two phase III MDA cluster randomized controlled trials (cRCT) will be conducted in Mozambique and in Kenya. Arms will either receive: 1) ivermectin 400 µg/kg single dose to humans; 2) ivermectin 400 µg/kg single dose to humans and livestock; or 3) albendazole 400 mg as control. The primary outcome is malaria infection incidence in children. In preparation for the BOHEMIA cRCT, a phase II clinical trial was carried out in Kilifi county in Kenya to evaluate the pharmacokinetics of two different ivermectin dose regimens. The mosquitocidal effect of ivermectin was assessed alongside the effect of albendazole to confirm its validity as a non-mosquitocidal de-worming control. Evidence from previous studies shows 300 µg/kg ivermectin given once daily for 3 days results in a significant reduction in mosquito survival up to 28 days. However, MDA strategies may operationally struggle to deliver high coverage and adherence rates using a 3 day regimen. For this reason, an open-label phase II RCT was designed to compare the population pharmacokinetics of single high-dose of ivermectin 400 µg/kg to the 3-day regimen of 300 µg/kg of ivermectin.
Methods: Healthy individuals from Kilifi county, Kenya (n=30) participated in the phase II clinical trial, randomized to receive either ivermectin single-dose (1x400 µg/kg, n=12), ivermectin on 3 consecutive days (3x300 µg/kg, n=6), albendazole single-dose (400 mg, n=6), or no treatment (n=6). Participants’ blood plasma was sampled regularly for up to 28 days (14 samples per patient over 7 days), and ivermectin was quantified by LC-MS/MS (3,4), then analysed by population pharmacokinetics analysis.
Results: The plasma pharmacokinetic parameters were as follows: apparent population clearance 7.1 L/h (interindividual variability: 0.42), central and peripheral volumes of distribution were 206 L (0.45) and 178 L (0.42), respectively. Body fat was the only covariate that significantly influenced the pharmacokinetic profile of ivermectin. The pharmacokinetic model accurately depicted population pharmacokinetics for oral ivermectin.
Conclusions: Ivermectin 1x400 µg/kg single dose strategy can be more attractive than 3x300 µg/kg as it produces similar exposure while maintaining easier feasibility of MDA campaigns, is more affordable, and is likely to yield higher compliance at the community level.
References:
[1] Chaccour C, Hammann F, Rabinovich NR. Ivermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety. Malar J. 2017 24;16(1):161.
[2] Chaccour C, Casellas A, Hammann F, Ruiz-Castillo P, Nicolas P, Montaña J, et al. BOHEMIA: Broad One Health Endectocide-based Malaria Intervention in Africa—a phase III cluster-randomized, open-label, clinical trial to study the safety and efficacy of ivermectin mass drug administration to reduce malaria transmission in two African settings. Trials. 2023 Feb 21;24(1):128.
[3] Duthaler U, Suenderhauf C, Karlsson MO, Hussner J, Meyer Zu Schwabedissen H, Krähenbühl S, et al. Population pharmacokinetics of oral ivermectin in venous plasma and dried blood spots in healthy volunteers. Br J Clin Pharmacol. 2019;85(3):626–33.
[4] Duthaler U, Suenderhauf C, Gaugler S, Vetter B, Krähenbühl S, Hammann F. Development and validation of an LC-MS/MS method for the analysis of ivermectin in plasma, whole blood, and dried blood spots using a fully automatic extraction system. J Pharm Biomed Anal. 2019 Aug 5;172:18–25.