Pharmacometric modelling to describe pharmacokinetics and exposure-response of ivermectin in adolescent patients infected with Trichuris trichiura
David Ajayi (1,2), Ochuko M. Orherhe (1,3), Goonaseelan (Colin) Pillai (1,4,5), Samer Mouksassi (1,6), Britta Steffens (7), Dominic Bräm (7), Viviane Sprecher (8,9), Daniela Hoffmann (8,9), Michael Buettcher (7,9,10), Jean T. Coulibaly (11,12), Said M. Ali (13), Jennifer Keiser (8,9), Marc Pfister (7,11)
(1) APT – Africa Fellowship Program, South Africa, (2) Chrisland University, Nigeria, (3) Obafemi Awolowo University, Nigeria, (4) University of Cape Town, South Africa, (5) CP+ Associates GmbH, Switzerland, (6) Certara, Egypt, (7) University Children Hospital of Basel, Switzerland, (8) Swiss Tropical and Public Health Institute, Switzerland, (9) University Hospital Basel, Switzerland, (10) University Lucerne, Switzerland, (11) Université Félix Houphouët-Boigny, Côte d’Ivoire, (12) Centre Suisse de Recherches Scientifiques en Côte d’Ivoire, Côte d’Ivoire, (13) Public Health Laboratory Ivo de Carneri, Zanzibar (Tanzania)
Introduction:
Soil-transmitted helminth infections are a major public health challenge in many tropical and subtropical low-income regions. Monotherapy with albendazole has shown good efficacy for roundworm and hookworm but not for Trichuris trichiura (whipworm) infection, for which the combination with ivermectin has been explored. Studies have shown that the efficacy of the combination therapy was significantly higher in Tanzania (Pemba Island) than in Côte d’Ivoire.
Objectives:
- Investigate the difference between the population pharmacokinetics (PK) of ivermectin when combined with albendazole in Tanzania and Côte d’Ivoire.
- Determine if an exposure-response analysis of ivermectin in combination with albendazole could explain the low efficacy in Côte d’Ivoire.
- Explore, using simulations, whether higher doses of ivermectin might have different outcomes.
Methods:
A total of 110 microsamples were collected in the framework of a randomized controlled trial from 24 adolescents with T. trichiura infection in Côte d’Ivoire and Tanzania, who were treated with a combination therapy of ivermectin and albendazole. A population PK model was developed with the Monolix 2023R1 software. A regression analysis was performed to investigate the relationship between egg reduction in the faeces and different exposure metrics of ivermectin and albendazole for each country. As exposure measures, peak concentration and AUC of ivermectin and of the active metabolite albendazole sulfoxide were investigated. Using simulations, exposure level of the current ivermectin dose (200 µg/kg) was compared to higher doses of ivermectin (400 and 600 µg/kg).
Results:
The PK profile of ivermectin was best described by a one-compartment model, first-order absorption, no delay in absorption, and allometric scaling of the weight on the volume and clearance parameters, with the weight centered at 50 kg. The model estimated an absorption rate constant of 0.26 h-1, a volume of distribution of 162.43 L, and a clearance of 7.82 L/h, with all the parameters estimated with high precision (% relative standard error < 50). The bivariate analysis did not show any statistically significant relationship between the response metric (cure) and the covariates. In Tanzania, all patients showed a very high egg reduction independent of exposure. In Côte d’Ivoire, a relationship was shown between higher exposure and egg reduction, although not statistically significant. Simulation with higher doses of 400 and 600 µg/kg ivermectin caused a significant reduction in the relative egg count by 90 % and 99 % respectively.
Conclusions:
A one-compartment model with first-order absorption and first-order elimination fitted the PK data of ivermectin collected from adolescent patients with T. trichiura in Tanzania and Côte d’Ivoire with good adequacy, with PK parameters not significantly different across both study sites. The relative egg count was significantly different between the two study sides, though. There was a relationship between the relative egg count and the peak concentration of ivermectin and albendazole sulfoxide in Côte d’Ivoire, although not statistically significant, suggesting the need for larger studies to confirm this exposure-response relationship.
References:
[1] Bethony J, Brooker S, Albonico M, et al. Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet. 2006;367(9521):1521-1532. doi:10.1016/S0140-6736(06)68653-4.
[2] Moser W, Schindler C, Keiser J. Efficacy of Recommended Drugs against Soil Transmitted Helminths: Systematic Review and Network Meta-Analysis. BMJ. 2017; 358, j4307. doi:10.1136/bmj.j4307
[3] Brussee JM, Schulz JD, Coulibaly JT, Keiser J, Pfister M. Ivermectin Dosing Strategy to Achieve Equivalent Exposure Coverage in Children and Adults. Clin Pharmacol Ther. 2019;106(3):661-667. doi:10.1002/cpt.1456
[4] Smit MR, Ochomo EO, Waterhouse D, et al. Pharmacokinetics-Pharmacodynamics of High-Dose Ivermectin with Dihydroartemisinin-Piperaquine on Mosquitocidal Activity and QT-Prolongation (IVERMAL). Clin Pharmacol Ther. 2019;105(2):388-401. doi:10.1002/cpt.1219
[5] Hürlimann E, Keller L, Patel C, et al. Efficacy and safety of co-administered ivermectin and albendazole in school-aged children and adults infected with Trichuris trichiura in Côte d'Ivoire, Laos, and Tanzania: a double-blind, parallel-group, phase 3, randomised controlled trial. Lancet Infect Dis. 2022;22(1):123-135. doi:10.1016/S1473-3099(21)00421-7
[6] Navarro M, Camprubí D, Requena-Méndez A, et al. Safety of high-dose ivermectin: a systematic review and meta-analysis. J Antimicrob Chemother. 2020;75(4):827-834. doi:10.1093/jac/dkz524
[7] Gwee A, Duffull S, Zhu X, et al. Population pharmacokinetics of ivermectin for the treatment of scabies in Indigenous Australian children. PLoS Negl Trop Dis. 2020;14(12):e0008886. Published 2020 Dec 7. doi:10.1371/journal.pntd.0008886
[8] Alshehri A, Chhonker YS, Bala V, et al. Population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis. PLoS Negl Trop Dis. 2023;17(6):e0011319. Published 2023 Jun 1. doi:10.1371/journal.pntd.0011319
[9] Schulz JD, Coulibaly JT, Schindler C, et al. Pharmacokinetics of ascending doses of ivermectin in Trichuris trichiura-infected children aged 2-12 years. The Journal of antimicrobial chemotherapy. 2019; 74(6): 1642–1647. https://doi.org/10.1093/jac/dkz083
[10] Matamoros G, Sánchez A, Gabrie JA, et al. Efficacy and Safety of Albendazole and High-Dose Ivermectin Co-administration in School-Aged Children Infected with Trichuris trichiura in Honduras: A Randomized Controlled Trial. Clin Infect Dis. 2021;73(7):1203-1210. doi:10.1093/cid/ciab365