Informing BOHEMIA cluster randomized controlled trial ivermectin dose selection in healthy participants in Kenya
Charlotte Kern, Yvonne Kamau, Kelly Ominde, Mercy Tuwei, Lawrence Babu, Jonathan Karisa, Jane Adetifa, Urs Duthaler, Carlos Chaccour, Marta Maia, Felix Hammann
University Hospital Bern (Switzerland), Kenya Medical Research Institute (KEMRI) Centre for Geographic and Medical Research (Kenya), Clinica Universidad de Navarra (Spain), Centro de Investigación Biomédica en Red de Enfermedades Infecciosas Madrid (Spain), ISGlobal & University of Barcelona (Spain), University Hospital Basel (Switzerland), University of Oxford (UK)
Objectives
A promising new strategy in malaria prevention is vector control through mass drug administration (MDA) of ivermectin, a broad-spectrum endectocide used to treat tropical diseases. Ivermectin’s mode of action is independent of vector behavior or insecticide resistance status, therefore having the potential to directly address malaria residual transmission (1). The BOHEMIA research consortium aims to evaluate the MDA of ivermectin for malaria control in Eastern Africa with two phase III cluster randomized controlled trials (2). Evidence from the IVERMAL study indicates that 300 µg/kg ivermectin given once a day for three 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 long regimen. Simple dosing schemes may be preferable if sufficiently effective concentrations can be maintained.
This study aims to provide evidence to inform the decision-making of the dose selection for BOHEMIA cluster randomized controlled trial, by describing the population pharmacokinetics of ivermectin during the first 7 days post-administration in a Kenyan population sample for field trial design. Therefore, an open-label phase II RCT was designed to compare the population pharmacokinetics of a single dose of ivermectin 400 µg/kg to the 3-day regimen of 300 µg/kg of ivermectin. Both dosing schemes are currently being evaluated for malaria vector control but single monthly doses offer considerable advantages with regards to organizational complexity and economics. A population pharmacokinetics model of ivermectin was built for both regimens, in plasma and dried blood spots (DBS), a sampling method better suited to field trials. The mosquitocidal effect of ivermectin was assessed alongside the effect of albendazole to confirm its validity as a non-mosquitocidal deworming control.
Methods
A total of 30 healthy adult volunteers participated, either taking ivermectin once (1x400 µg/kg, n=12), on three consecutive days (3x300 µg/kg, n=6), albendazole once (400 mg, n=6) or no treatment (n=6) at all (placebo control). Participants blood plasma (14 samples/patient over 7 days) and capillary blood from dried blood spots (DBS) on filter paper (9 samples/patient over 4 days) were sampled. Ivermectin was quantified by liquid chromatography tandem mass spectrometry in plasma and also in DBS, using a fully automated extraction system (3,4). Population pharmacokinetics analysis with step-wise covariate modelling of plasma and DBS concentrations, and trial simulations were performed with NONMEM.
Results
A two-compartment model with a transit absorption model and first-order elimination best characterized the data. For an individual weighing 70 kg, the model estimated the apparent population clearance to be 14.19 L/h with 54% inter-individual variability. The central and peripheral volumes of distribution were estimated at 366.80 L (67% variability) and 517.5 L (48% variability), respectively. Additionally, there was a strong linear correlation (R² = 0.93) between concentrations measured in DBS and plasma samples. The concentrations from DBS samples were, on average, 55.5% lower than those in plasma.
Conclusion
We were able to show that DBS concentrations correlate strongly with plasma concentrations in the participants in Kenya, and that DBS sampling could therefore be used in settings where peripheral venous sampling is impractical and costly, such as in large MDA field studies as BOHEMIA. A similar ivermectin drug exposure was achieved with the two ivermectin regimens investigated, with comparable ranges of total exposure (AUClast) and Cmax in blood plasma. Moreover, albendazole was validated as a non-mosquitocidal deworming control. Administering a single dose of ivermectin offers multiple advantages. Firstly, it simplifies mass drug administration campaigns by reducing the amount of medication distributed while still maintaining effective drug exposure, leading to more straightforward implementation and lower operational costs. Secondly, a single dose strategy is more likely to increase community members’ compliance.
References:
- 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.
- 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.
- 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.
- 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.