Richard M. Hoglund (1,2), Borimas Hanboonkunupakarn (1,5), Kevin C. Kobylinski (3), Phornpimon Tipthara Wong (1), Benjamas Sriburin (1), Podjanee Jittamala (4), Nicholas P.J. Day (1,2), Nicholas J. White (1,2), Joel Tarning (1,2)
(1) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, (2) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (3) Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. (4) Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. (5) Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
Objectives: Ivermectin is a drug which has been used in the treatment of several different diseases. It has also been shown that ivermectin has mosquito-lethal properties, which could be used in future mass drug administrations trials with the aim to eradicate malaria. To be able to optimise such trials, it is important to understand the pharmacokinetic properties of both ivermectin and its metabolites and the relationship between drug exposure and the mosquito-lethal effect. Therefore, the objective of this study was to develop a pharmacokinetic-pharmacodynamic model which can be used to predict mosquito mortality after treatment with ivermectin.
Methods: The pharmacokinetic and pharmacodynamic models were constructed using dense data from two healthy volunteer trials conducted in Bangkok, Thailand. The first study was a healthy volunteer cross-over trial (n = 16) investigating potential drug-drug interactions between ivermectin, dihydroartemisinin-piperaquine, and primaquine [1]. The second study was a study in healthy volunteers (n = 10) designed to measure the metabolites of ivermectin. Dense pharmacokinetic samples were collected in both studies and the levels of ivermectin and three metabolites [2] were quantified at the department of clinical Pharmacology, MORU, Bangkok. In addition to the pharmacokinetic data, blood from the volunteers were fed to mosquitos using two different techniques (membrane feeding and direct feeding) and the mosquito mortality in two different mosquito species (anopheles dirus and anopheles minimus) were measured. Separate pharmacokinetic-pharmacodyanmic models were developed for two species. The collected data was used to develop pharmacokinetic and pharmacodynamic models in NONMEM.
Results: The pharmacokinetic properties of ivermectin and its metabolites were successfully described by the developed population pharmacokinetic model. The model described the observed data adequately and showed good predictive performance. Body weight was added as covariate in the model using an allometric function. It was also shown that the absorption of ivermectin were altered when administered together with dihydroartemisinin-piperaquine. The pharmacokinetic model was fixed and linked to a population pharmacodynamic model describing mosquito mortality. The pharmacodynamic model consisted of an Emax-model with an estimated baseline mosquito mortality. The sum of the molar concentrations of ivermectin and its three metabolites were used to drive the effect. This pharmacokinetic-pharmacodynamic model successfully described the observed concentration measurements of ivermectin and its metabolites, as well as their relationship to mosquito mortality. Anopheles minimus was substantially more sensitive to ivermectin compared to anopheles dirus. The developed model was used to simulate different administration scenarios.
Conclusions: A pharmacokinetic-pharmacodynamic model was developed successfully. This model was used to simulate several different dosing scenarios of ivermectin treatment and mass drug administration. This model could also be used to inform the design of future clinical trials.
References:
[1] Kobylinski KC, Jittamala P, Hanboonkunupakarn B, et al. Safety, Pharmacokinetics, and Mosquito-Lethal Effects of Ivermectin in Combination With Dihydroartemisinin-Piperaquine and Primaquine in Healthy Adult Thai Subjects. Clin Pharmacol Ther. 2020;107(5):1221-1230. doi:10.1002/cpt.1716
[2] Tipthara P, Kobylinski KC, Godejohann M, Hanboonkunupakarn B, Roth A, Adams JH, White NJ, Jittamala P, Day NPJ, Tarning J. Identification of the metabolites of ivermectin in humans. Pharmacol Res Perspect. 2021 Feb;9(1):e00712. doi: 10.1002/prp2.712.
Reference: PAGE 29 (2021) Abstr 9850 [www.page-meeting.org/?abstract=9850]
Poster: Drug/Disease Modelling - Infection