TY - JOUR T1 - A pharmacokinetic-pharmacodynamic assessment of the hepatic and bone-marrow toxicities of the new trypanoside fexinidazole JF - bioRxiv DO - 10.1101/486761 SP - 486761 AU - James A Watson AU - Nathalie Strub-Wourgraft AU - Antoine Tarral AU - Isabela Ribeiro AU - Joel Tarning AU - Nicholas J White Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/12/04/486761.abstract N2 - Fexinidazole is a novel oral treatment for Trypanosoma brucei gambiense human African trypanosomiasis: g-HAT. Fexinidazole is also active against other kinetoplastid parasites, notably 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 chronic Chagas disease and g-HAT, in order to assess the determinants of toxicity.A population pharmacokinetic model was fitted to plasma concentration data on the bioactive fexinidazole sulfone metabolite from three phase 1 studies, two g-HAT phase 2/3 field trials and one Chagas phase 2 field trial (462 individuals in total). Bayesian exposure-response models were then fitted to hematological and liver related pharmacodynamic outcomes in chronic 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 chronic Chagas disease. Clinically insignificant transient reductions in neutrophil and platelet counts consistent with these exposure-response relationships were observed in the g-HAT trials. In contrast, no evidence of hepatotoxicity was observed in the g-HAT trials.Fexinidazole treatment results in a dose dependent liver toxicity and transient bone marrow suppression in Chagas disease. Regimens of shorter duration should be trialled 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.AbbreviationsALTalanine aminotransferaseASTaspartate aminotransferaseAUlogCarea under the log plasma concentration time curveCNScentral nervous systemCSFcerebrospinal fluidDBSdry blood spotg-HATTrypanosoma brucei gambiense human African trypanosomiasisM2fexinidazole sulfone metaboliteNECTNifurtimox-Eflornithine combination therapyNHVnormal healthy volunteersOVLoverlapping coefficientPK-PDpharmacokinetics-pharmacodynamics ER -