Antileishmanial Efficacy and Pharmacokinetics of DB766-Azole Combinations

Abstract

Given the limitations of current antileishmanial drugs and the utility of oral combination therapy for other infections, developing an oral combination against visceral leishmaniasis should be a high priority. combination studies with DB766 and antifungal azoles against intracellular showed that posaconazole and ketoconazole, but not fluconazole, enhanced DB766 potency. Pharmacokinetic analysis of DB766-azole combinations in uninfected Swiss Webster mice revealed that DB766 exposure was increased by higher posaconazole and ketoconazole doses, while DB766 decreased ketoconazole exposure. In -infected BALB/c mice, DB766-posaconazole combinations given orally for 5 days were more effective than DB766 or posaconazole alone. For example, 81% ± 1% (means ± standard errors) inhibition of liver parasite burden was observed for 37.5 mg/kg of body weight DB766 plus 15 mg/kg posaconazole, while 37.5 mg/kg DB766 and 15 mg/kg posaconazole administered as monotherapy gave 40% ± 5% and 21% ± 3% inhibition, respectively. Combination index (CI) analysis indicated that synergy or moderate synergy was observed in six of nine combined dose groups, while the other three were nearly additive. Liver concentrations of DB766 and posaconazole increased in almost all combination groups compared to monotherapy groups, although many increases were not statistically significant. For DB766-ketoconazole combinations evaluated in this model, two were antagonistic, one displayed synergy, and one was nearly additive. These data indicate that the efficacy of DB766-posaconazole and DB766-ketoconazole combinations is influenced in part by the pharmacokinetics of the combination, and that the former combination deserves further consideration in developing new treatment strategies against visceral leishmaniasis.

CYP51 as drug targets for fungi and protozoan parasites: past, present and future

“…If so, much more efficient azole-based drugs or rather drug combination would be required to produce a prompt cytocidal effect in Leishmania (Lepesheva et al 2015). Promising results of combination therapy using allopurinol and ketoconazole (Halim et al 1993) or amphotericin B and fluconazole (Horber et al 1993) (visceral leishmaniasis in human) as well as 81% reduction of the parasite burden in L. donovani -infected mice treated with combination of posaconazole and arylimidamide DB766 (Joice et al 2017) support this notion.…”

Recent strategies for the development of oral medicines for the treatment of visceral leishmaniasis

“…Due to the relatively low efficacies of some new molecules studied against VL, the combination therapy strategy has been used to test the effectiveness of association with other drugs. In a recent research, compound DB766 (bis‐arylimidamide) was associated with azole antifungals, because azole antifungals decrease the expression of CYP5122A1 protein, part of the ergosterol metabolism, while the DB766 seems to cause changes in the mitochondria, nucleus and microtubules (Joice et al, 2018). In vitro assays against intracellular L. donovani amastigote forms, the combination of DB766 with 4 μM posaconazole and 20 μM ketoconazole improved the potency of DB766, reducing its IC 50 to approximately 10 nM.…”

XRCC1‐mediated DNA repair is associated with progression‐free survival of multiple myeloma patients after autologous stem cell transplant

“…Assays were performed in triplicate at least twice. Absolute IC 50 values (the concentration of melphalan required to inhibit 50% of the cell viability) were determined using KaleidaGraph software (Synergy Software, Reading, PA) as previously described …”