A pharmacokinetic-pharmacodynamic assessment of the hepatic and bone-marrow toxicities of the new trypanoside fexinidazole.
Watson JA., Strub-Wourgraft N., Tarral A., Ribeiro I., Tarning J., White NJ.
Fexinidazole is a novel oral treatment for Trypanosoma brucei gambiense, human African trypanosomiasis: g-HAT. Fexinidazole also has activity against T. cruzi the causative agent of Chagas disease. During the course of a dose ranging assessment in 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 = 4549) 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 phase 2 field trial (n = 462 individuals total). Bayesian exposure-response models were then fitted to hematological and liver related pharmacodynamic outcomes in Chagas patients.Neutropenia, reductions in platelet counts, and elevations in liver transaminases were all found to be exposure 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 g-HAT. In contrast, no evidence of hepatotoxicity was observed in g-HAT.Fexinidazole treatment results in a dose-dependent liver toxicity and transient bone marrow suppression in Chagas disease. Regimens of shorter duration should be trialed for Chagas. The currently recommended regimen for sleeping sickness provides exposures within a satisfactory safety margin for bone marrow suppression and does not cause hepatotoxicity.