title: Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease.
abstract: Two CYP51 inhibitors, posaconazole and the ravuconazole prodrug E1224, were recently tested in clinical trials for efficacy in indeterminate Chagas disease. The results from these studies show that both drugs cleared parasites from the blood of infected patients at the end of the treatment but that parasitemia rebounded over the following months. In the current study, we sought to identify a dosing regimen of posaconazole that could permanently clear Trypanosoma cruzi from mice with experimental Chagas disease. Infected mice were treated with posaconazole or benznidazole, an established Chagas disease drug, and parasitological cure was defined as an absence of parasitemia recrudescence after immunosuppression. Twenty-day therapy with benznidazole (10 to 100 mg/kg of body weight/day) resulted in a dose-dependent increase in antiparasitic activity, and the 100-mg/kg regimen effected parasitological cure in all treated mice. In contrast, all mice remained infected after a 25-day treatment with posaconazole at all tested doses (10 to 100 mg/kg/day). Further extension of posaconazole therapy to 40 days resulted in only a marginal improvement of treatment outcome. We also observed similar differences in antiparasitic activity between benznidazole and posaconazole in acute T. cruzi heart infections. While benznidazole induced rapid, dose-dependent reductions in heart parasite burdens, the antiparasitic activity of posaconazole plateaued at low doses (3 to 10 mg/kg/day) despite increasing drug exposure in plasma. These observations are in good agreement with the outcomes of recent phase 2 trials with posaconazole and suggest that the efficacy models combined with the pharmacokinetic analysis employed here will be useful in predicting clinical outcomes of new drug candidates.
authors.affiliation: Department of Genetics and Neglected Diseases, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Khare
authors.affiliation: Department of Genetics and Neglected Diseases, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Monique
authors.initials: M
authors.lastname: Stinson
authors.affiliation: Department of Pharmacology, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Ianne
authors.initials: I
authors.lastname: Rivera
authors.affiliation: Department of Metabolism and Pharmacokinetics, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Groessl
authors.affiliation: Department of Metabolism and Pharmacokinetics, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.affiliation: Department of Medicinal Chemistry, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Vince
authors.initials: V
authors.lastname: Yeh
authors.affiliation: Department of Pharmacology, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Wen
authors.affiliation: Department of Medicinal Chemistry, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Molteni
authors.affiliation: Department of Genetics and Neglected Diseases, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Glynne
authors.affiliation: Department of Genetics and Neglected Diseases, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA fsupek@gnf.org.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Supek
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000469:parasitology; D017322:Clinical Trials, Phase II as Topic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006321:Heart / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D007165:Immunosuppression Therapy; D051379:Mice; D041681:NIH 3T3 Cells; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D018512:Parasitemia / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000469:parasitology; D012008:Recurrence; D058886:Sterol 14-Demethylase / Q000378:metabolism; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology
chemical_list: D058888:14-alpha Demethylase Inhibitors; D009593:Nitroimidazoles; D014230:Triazoles; D014344:Trypanocidal Agents; C101425:posaconazole; D058886:Sterol 14-Demethylase; C009999:benzonidazole