DOI: 10.1101/486761Dec 4, 2018Paper

A pharmacokinetic-pharmacodynamic assessment of the hepatic and bone-marrow toxicities of the new trypanoside fexinidazole

BioRxiv : the Preprint Server for Biology
James Andrew WatsonNicholas J White


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 I studies, two g -HAT phase II/III field trials and one Chagas phase-II field trial (n=462 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. Clinica...Continue Reading

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Aspartate Transaminase
Blood Platelets
Bone Marrow
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