Pharmacokinetic-Pharmacodynamic Assessment of the Hepatic and Bone Marrow Toxicities of the New Trypanoside Fexinidazole

Abstract

Fexinidazole is a novel oral treatment for human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT). Fexinidazole also has activity against T. cruzi, the causative agent of Chagas disease. During the course of a dose ranging assessment in patients with chronic indeterminate Chagas disease, delayed neutropenia and significant increases in hepatic transaminases were observed and clinical investigations were suspended. We retrospectively analyzed all available pharmacokinetic and pharmacodynamic data on fexinidazole in normal healthy volunteers and in patients with Chagas disease and g-HAT to assess the determinants of toxicity. A population pharmacokinetic model was fitted to plasma concentrations (n = 4,549) of the bioactive fexinidazole sulfone metabolite, accounting for the majority of the bioactive exposure, from three phase 1 studies, two g-HAT phase 2/3 field trials, and one Chagas disease phase 2 field trial (n = 462 individuals in total). Bayesian exposure-response models were then fitted to hematological and liver-related pharmacodynamic outcomes in Chagas disease patients. Neutropenia, reductions in platelet counts, and elevations in liver transaminases were all found to be exposure dependent and, thus, dose dependent in patients with Chagas disease. Clinically insignificant transient reductions in neutrophil and platelet counts consistent with these exposure-response relationships were observed in patients with g-HAT. In contrast, no evidence of hepatotoxicity was observed in patients with g-HAT. Fexinidazole treatment results in a dose-dependent liver toxicity and transient bone marrow suppression in Chagas disease patients. Regimens of shorter duration should be evaluated in clinical trials with patients with Chagas disease. The currently recommended regimen for sleeping sickness provides exposures within a satisfactory safety margin for bone marrow suppression and does not cause hepatotoxicity.

Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy

“…One encouraging result is that the repositioned antimicrobial agent fexinidazole (6), a safe and effective newly approved drug for late-stage human African trypanosomiasis (HAT) [13], has shown curative activity potentially better than 1 in acute stage CD mouse models and equivalent to 1 in the chronic stage models, as revealed by highly sensitive bioluminescence imaging [14]. Although a phase II proof of concept clinical study of 6 was interrupted because of safety and tolerability issues at higher doses and longer treatment times, good efficacy against CD was observed at more tolerable doses; therefore, a second clinical trial has been initiated [15,16]. A close analogue of the HAT clinical candidate SCYX-7158 (7), oxaborole SCYX-6759 (8), also exhibited strong in vivo activity against CD but was not curative in the chronic model [17].…”

Current trends in the pharmacological management of Chagas disease

“…Of interest, fexinidazole has been approved by the European Medianes Agency (EMA) for the treatment of African Trypanosomiasis, in both adults and children (Deeks, 2019), thus demonstrating its therapeutic potential to be applied to CD. Probably, dose and treatment time adjustments may be required for clinical trials (Watson et al, 2019).…”

Review of pharmacological options for the treatment of Chagas disease

“…Ergosterol biosynthesis enzymes in particular have been well studied, and CYP51 (sterol 14-Demethylase) was proposed as an interesting target, both due to its importance in parasite survival, and the availability of multiple medications already in the market (i.e. azole antifungal drugs) that could be easily repositioned for clinical trials in CD 104,[131][132][133][134] . This repositioning approach is advantageous in view of the cost and time-consuming process required compared to the development of new medicines, especially in neglected diseases, since repositioned drugs already have their toxicological and pharmacokinetic profile assessed when used on their previous therapeutic target 135 .…”

“…Fexinidazole is a drug previously repositioned for Trypanosoma brucei gambiense infection (African trypanosomiasis) after demonstrating effectiveness in a randomized controlled trial 145 . Also, fexinidazole`s safety and pharmacokinetics had been properly studied in humans, proving that oral administration is safe and well tolerated 132,133,146 . Considering this drug is effective in clearing T.cruzi as well in pre-clinical studies, an ongoing randomized, double-blind, placebo controlled trial is being carried out in Argentina, Bolivia and Spain to assess its efficacy in CD (NCT02498782).…”