Urs Duthaler (1), Michael Weber (1), Lorenz Hofer (2,3), Beatrice Vetter (1), Marta Maia Ferreira (4, 5), Pie Müller (2, 3), Stephan Krähenbühl (1), Felix Hammann (6, 7)
(1) Division of Clinical Pharmacology & Toxicology, Department of Biomedicine, University and University Hospital Basel, Switzerland, (2) Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland, (3) University of Basel, Basel, Switzerland, (4) KEMRI Wellcome Trust Research Programme, P.O. Box 230, Kilifi, 80108, Kenya, (5) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Old Road Campus Roosevelt Drive, Oxford, OX3 7FZ, UK, (6) Division of Clinical Pharmacology & Toxicology, Department of Internal Medicine, University Hospital Bern, Switzerland, (7) Institute of Pharmacology, University of Bern, Bern, Switzerland.
Introduction: The World Health Organization (WHO) estimates vector-borne diseases to account for more than 17% of infectious diseases [1]. Globally, mosquitoes are the most important disease vectors transmitting infectious diseases such as malaria or dengue that are a major threat to global health. A novel approach in vector control are mass drug administrations (MDAs) of endectocides such as ivermectin (IVM). Preliminary data show that IVM could effectively disrupt the spread of disease and decrease the incidence of malaria by diminishing the vector population [2, 3]. Drug-drug interactions of IVM with pharmacotherapy against co-endemic diseases (e.g. tuberculosis, HIV/AIDS) might interfere with the efficacy and safety of MDAs. These interactions may not only occur in the host but possibly also in the mosquito vector [4]. A mosquito animal model for pharmacokinetic studies would therefore be desirable to design more effective MDAs.
Objectives:
- Establish a bioanalytical workflow to determine IVM in Aedes aegypti
- Create a model to describe IVM pharmacokinetics and drug interactions with IVM in the mosquito
Methods: Female Aedes aegypti mosquitoes, globally the key vector for dengue, were allowed to feed on blood spiked with ivermectin alone or IVM in combination with one of the following small-molecular drugs: rifampin, ketoconazole, ritonavir, or piperonyl butoxide (PBO). Aedes was the preferred animal model because of its importance as a vector and its comparatively low sensitivity to IVM. This allows for higher concentrations of IVM in blood meals which in turn simplifies the bioanalysis. The combination drugs were chosen because they may either be medications for co-endemic infectious diseases or a common bed-net treatment (PBO). Mosquitoes were frozen at scheduled time-points post-treatment, weighed, and analyzed by LC-MS/MS. Since it is not possible to obtain systemic circulating concentrations in the animals, we analyzed the pharmacokinetic profiles of IVM as whole body drug amounts per mosquito. We evaluated several structural models (one to three compartments, and zero-order, first-order, and Michaelis-Menten elimination), as well as covariate effects. Lastly, the impact of the treatments on mosquito survival was examined.
Results: We included 960 samples from 960 individuals available for analysis, covering the first 48 hours post feeding. We demonstrated that mosquitoes can be dosed with high precision (CV% <15%, n=30) over a range of 10-1000 ng/mL IVM (R2: 0.99). An inter-batch analysis of ivermectin treatments revealed comparable long-lasting exposures with an estimated elimination half-life of 23.5±0.81 h.
The final structural model was a single compartment model with zero-order elimination and a lag term on elimination. Weight was an informative covariate on the elimination rate and the total amount of IVM ingested. The latter also showed inter-occasion variability, i.e. the volume of blood meals varied from batch to batch. The co-administration of ritonavir significantly increased the ivermectin exposure by 30%, whereas other drugs investigated did not interact with ivermectin PK. Intriguingly, increased exposure was caused by a prolongation of the initial lag time of about 12 h, whereas the terminal elimination rate remained similar. Importantly, the combination treatment enhanced the overall mortality rate by 25% compared to single treatments, and decreased fecundity.
Conclusions: Concentration-time profiles of small molecule drugs can be obtained from Aedes aegypti as an animal model. Pharmacometric modeling allows the estimation of primary pharmacokinetic parameters and the assessment of drug-drug interactions in mosquitoes.
References:
[1] https://www.who.int/news-room/fact-sheets/detail/vector-borne-diseases
[2] J Infect Dis, 210(12): 1972-80
[3] Lancet Infect Dis, 18(6): 615-626
[4] Drug Saf, 42(6): 743-750
Reference: PAGE () Abstr 9287 [www.page-meeting.org/?abstract=9287]
Poster: Drug/Disease Modelling - Other Topics