Population pharmacokinetics of benznidazole as monotherapy and in combination with fosravuconazole in adult patients with chronic Chagas disease (BENDITA study)
Frauke Assmus (1,2), Richard M. Hoglund (1,2), James Watson (1,2), Nicholas J. White (1,2), Ivan Scandale (3), Eric Chatelain (3), Sergio Sosa Estani (3), Fabiana Barreira (3), Bethania Blum de Oliveira (3), Tayná Marques (3), Danilo Bedor (4), Joel Tarning (1,2), and the BENDITA study group
(1) Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Thailand, (2) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom. (3) Drugs for Neglected Disease initiative, Switzerland, (4) Universidade Federal de Pernambuco, Brazil
Introduction: Chagas disease (American trypanosomiasis) is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi and can lead to potentially fatal cardiac and gastrointestinal complications [1]. Benznidazole is the first-line therapy, but has severe limitations such as long treatment duration (30-60 days), poor tolerability (especially in adult patients), poor compliance and questionable efficiency in the chronic stage of Chagas disease [2]. New treatment regimens are therefore currently investigated following two strategies [3]: i) shorter or reduced regimens of benznidazole to improve tolerability while maintaining efficacy; and ii) combination therapy with fosravuconazole, a prodrug with antitrypanosomal activity [4, 5]. Hitherto, information on benznidzole pharmacokinetics is scarce [6, 7] and there are no published studies yet on the impact of fosravuconazole on benznidazole pharmacokinetics, resulting in a limited understanding of the PK/PD relationships.
Objectives: The aim of this study was to characterize the population pharmacokinetic properties of benznidazole in adult patients with chronic Chagas disease receiving new treatment regimens and to investigate potential drug–drug interactions with fosravuconazole.
Methods: A total of 180 adults (aged 18 – 50 years) with chronic indeterminate Chagas disease enrolled in the BENDITA study [3] were included in the PK analysis. BENDITA is a double-blind, double-dummy, phase 2, multicentre, randomised trial in three outpatient units in Bolivia (ClinicalTrials.gov, NCT03378661). Sparse whole blood benznidazole concentration-time data was available from six treatment arms (30 subjects per group): 300 mg benznidazole daily for 8 weeks, 4 weeks, or 2 weeks; 150 mg benznidazole daily for 4 weeks; 150 mg benznidazole daily for 4 weeks plus fosravuconazole; or 300 mg benznidazole once per week for 8 weeks plus fosravuconazole (oral administration). All cohorts were pooled and analyzed using nonlinear mixed-effects modeling (NONMEM v.7.4). Different absorption, disposition, variability and covariate models were evaluated, along with various approaches for handling data below the quantification limit (BQL)[8].
Results: Benznidazole pharmacokinetics was dose-linear and well described by a transit-absorption model, followed by a one-compartment disposition model. Body weight was implemented as an allometric function on clearance and volume of distribution. Coadministration of fosravuconazole increased benznidazole clearance significantly (P ≤ 0.001) with a corresponding decrease in benznidazole exposure. However, this effect was not clinically relevant (< 20%). These findings were consistent and independent of the method used to handle data below the lower limit of quantification (M1 or M3).
Conclusions: In summary, population pharmacokinetics of benznidazole following different treatment regimens in adult chronic Chagas disease patients were successfully described. To the best of our knowledge, this is largest population PK analysis of benznidazole to date. Our results provide the basis for the further exploration of benznidazole exposure - parasitological response relationships and the selection of optimized dosing regimens for the treatment of chronic Chagas disease.
References:
[1] WHO World Health Organization. Chagas disease 2 April 2020 [Available from: https://www.who.int/news-room/facts-in-pictures/detail/chagas-disease.
[2] Pérez-Molina JA, Pérez-Ayala A, Moreno S, Fernández-González MC, Zamora J, López-Velez R. Use of benznidazole to treat chronic Chagas' disease: a systematic review with a meta-analysis. The Journal of antimicrobial chemotherapy. 2009;64(6):1139-47.
[3] Torrico F, Gascón J, Barreira F, Blum B, Almeida IC, Alonso-Vega C, et al. New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial. The Lancet Infectious diseases. 2021.
[4] Diniz LF, Mazzeti AL, Caldas IS, Ribeiro I, Bahia MT. Outcome of E1224-Benznidazole Combination Treatment for Infection with a Multidrug-Resistant Trypanosoma cruzi Strain in Mice. Antimicrobial agents and chemotherapy. 2018;62(6).
[5] Torrico F, Gascon J, Ortiz L, Alonso-Vega C, Pinazo MJ, Schijman A, et al. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. The Lancet Infectious diseases. 2018;18(4):419-30.
[6] Wiens MO, Kanters S, Mills E, Peregrina Lucano AA, Gold S, Ayers D, et al. Systematic Review and Meta-analysis of the Pharmacokinetics of Benznidazole in the Treatment of Chagas Disease. Antimicrobial agents and chemotherapy. 2016;60(12):7035-42.
[7] Molina I, Salvador F, Sánchez-Montalvá A, Artaza MA, Moreno R, Perin L, et al. Pharmacokinetics of Benznidazole in Healthy Volunteers and Implications in Future Clinical Trials. Antimicrobial agents and chemotherapy. 2017;61(4).
[8] Beal SL. Ways to fit a PK model with some data below the quantification limit. Journal of pharmacokinetics and pharmacodynamics. 2001;28(5):481-504.
