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.

Reply to “Drug Susceptibility of Genetically Engineered Trypanosoma cruzi Strains and Sterile Cure in Animal Models as a Criterion for Potential Clinical Efficacy of Anti-T. cruzi Drugs”

“…The 50% inhibitory concentration for intracellular amastigote forms was 1.2 M (unpublished data), not significantly different from that for the wild type and well within the normal range reported elsewhere for T. cruzi CL and other diverse strains (3). (iv) Our treatment data are consistent with findings reported in a recent paper (4). Using PCR to assess drug efficacy, these authors find that treatment of T. cruzi CL-infected mice with 100 mg/kg benznidazole for 20 days results in a complete cure.…”

“…However, it is unlikely that any new treatment for T. cruzi infection will be licensed unless it can achieve a sterile cure. Unfortunately, based on in vitro studies (3), in vivo assessment (1,4), and a clinical trial (2), posaconazole does not seem to meet this benchmark.…”

Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

“…The pharmacokinetic properties of GNF compounds and calculation of pharmacokinetic parameters was performed as described previously 23 . Mean compound plasma concentrations were calculated from fitted functions approximating compound plasma profile throughout 8 days of dosing.…”

“…However, benznidazole has side-effects that frequently lead to treatment interruption 18,20–22 and a better tolerated drug is needed. To model treatment in the indeterminate disease stage, we infected mice with T. cruzi parasites and began treatment 35 days after infection, when the immune system of the mice had controlled parasite burden 23 . We increased the parasite detection sensitivity by immunosuppressing the mice after 20 days of treatment 23,24 .…”

“…To model treatment in the indeterminate disease stage, we infected mice with T. cruzi parasites and began treatment 35 days after infection, when the immune system of the mice had controlled parasite burden 23 . We increased the parasite detection sensitivity by immunosuppressing the mice after 20 days of treatment 23,24 . In this model, GNF6702 dosed twice-daily at 10 mg/kg matched the efficacy of benznidazole at 100 mg/kg once-daily; all but one treated mice had no detectable parasites in blood, colon or heart tissue, even after 4 weeks of immunosuppression (Fig.…”