Treatment of experimental visceral leishmaniasis with single-dose liposomal amphotericin B - pharmacodynamics and biodistribution at different stages of disease [PublishAheadOfPrint]

Visceral leishmaniasis is a neglected tropical disease, which causes significant morbidity and mortality worldwide. Characterising the pharmacokinetics and pharmacodynamics of anti-leishmanial drugs in pre-clinical models is important for drug development and use. Here we investigated the pharmacodynamics and drug distribution of AmBisome® in L. donovani infected BALB/c mice at three different dose levels and two different time points after infection. We additionally compared drug levels in plasma, liver and spleen in infected and uninfected BALB/c mice over time. At the highest administered dose of 10 mg/kg AmBisome® >90% parasite inhibition was observed within 2 days after drug administration, consistent with drug distribution from blood to tissue within 24 hours and a fast rate of kill. Decreased drug potency was observed in the spleen when AmBisome® was administered on day 35 after infection, compared to day 14 after infection. Amphotericin B concentrations and total drug amounts per organ were lower in liver and spleen when AmBisome® was administered at the advanced stage of infection and when compared to uninfected BALB/c mice. However, the magnitude of difference was lower when total drug amounts per organ were estimated. Differences were also noted in drug distribution to L. donovani infected livers and spleens. Taken together our data suggests that organ enlargement and other pathophysiological factors cause infection- and organ-specific drug distribution and elimination after administration of single dose AmBisome® to L. donovani infected mice. Plasma levels were not reflective of changes in drug levels in tissues.

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