Antileishmanial Efficacy and Pharmacokinetics of DB766-Azole Combinations

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Issue Date
2017-10-23Author
Joice, April C.
Yang, Sihyung
Farahat, Abdelbasset A.
Meeds, Heidi
Feng, Mei
Li, Junan
Boykin, David W.
Wang, Michael Zhuo
Werbovetz, Karl A.
Publisher
American Society for Microbiology
Type
Article
Article Version
Scholarly/refereed, publisher version
Rights
© 2017 American Society for Microbiology. All Rights Reserved. Address correspondence to Michael Zhuo Wang, michael.wang@ku.edu, or Karl A. Werbovetz, werbovetz.1@osu.edu.A.C.J. and S.Y. contributed equally to this work.
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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. In vitro combination studies with DB766 and antifungal azoles against intracellular Leishmania donovani 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 L. donovani-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 in vivo 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.
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Citation
Joice AC, Yang S, Farahat AA, Meeds H, Feng M, Li J, Boykin DW, Wang MZ, Werbovetz KA. 2018. Antileishmanial efficacy
and pharmacokinetics of DB766-azole combinations. Antimicrob Agents Chemother 62:e01129-17. https://doi.org/10.1128/AAC
.01129-17.
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