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

Antimicrobial Agents and Chemotherapy
James A WatsonNicholas J White

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, th...Continue Reading

References

Nov 10, 1979·British Medical Journal·R WindleP R Bell
Jan 1, 1985·Annales Françaises D'anesthèsie Et De Rèanimation·C MartinF Gouin
Jun 1, 1980·The Journal of Infectious Diseases·R SaginurJ G Bartlett
Jan 8, 2004·Liver International : Official Journal of the International Association for the Study of the Liver·Fehmi TabakHakan Senturk
Feb 18, 2006·Transactions of the Royal Society of Tropical Medicine and Hygiene·Jacques Pépin, Bokelo Mpia
Nov 9, 2007·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Gerardo PriottoUnni Karunakara
Feb 4, 2012·Science Translational Medicine·Susan WyllieA H Fairlamb
Jun 14, 2012·Journal of Clinical Gastroenterology·Yusuf CoskunIlhami Yüksel
Oct 22, 2013·Parasite : Journal De La Société Française De Parasitologie·Mariette DethouaPhilippe Vincendeau

Citations

Jul 9, 2020·Expert Opinion on Investigational Drugs·Nieves Martínez-PeinadoJulio Alonso-Padilla
Dec 15, 2020·British Journal of Clinical Pharmacology·Fernanda LascanoJaime Altcheh

Methods Mentioned

BETA
PCR

Clinical Trials Mentioned

NCT00982904
NCT01340157
NCT01685827
NCT02169557
NCT02184689
NCT02498782

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