Anti-Trypanosomal Treatment with Benznidazole is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease.

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Anti-Trypanosomal Treatment with Benznidazole is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease.

Antimicrob Agents Chemother. 2015 Aug 3;

Authors: Khare S, Liu X, Stinson M, Rivera I, Groessl T, Tuntland T, Yeh V, Wen B, Molteni V, Glynne R, Supek F

Abstract
Two CYP51 inhibitors, posaconazole and 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 T. 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 (10-100 mg/kg/day) resulted in a dose-dependent increase in antiparasitic activity, and the 100 mg/kg regimen effected parasitological cure in all treated mice. By contrast, all mice remained infected after a 25-day treatment with posaconazole at all tested doses (10-100 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 reduction in heart parasite burden, the antiparasitic activity of posaconazole plateaued at low doses (3-10 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 pharmacokinetic analysis employed here will be useful in predicting clinical outcomes of new drug candidates.

PMID: 26239982 [PubMed - as supplied by publisher]