Wijnant, G-J;
Van Bocxlaer, K;
Yardley, V;
Harris, A;
Murdan, S;
Croft, SL;
(2018)
Relation between Skin Pharmacokinetics and Efficacy in AmBisome Treatment of Murine Cutaneous Leishmaniasis.
Antimicrobial Agents and Chemotherapy
, 62
(3)
, Article e02009-17. 10.1128/AAC.02009-17.
Preview |
Text
Murdan Relation between Skin Pharmacokinetics and Efficacy in AmBisome Treatment of Murine Cutaneous Leishmaniasis.pdf - Published Version Download (672kB) | Preview |
Abstract
AmBisome® (LAmB), a liposomal formulation of amphotericin B (AmB), is a second-line treatment for the parasitic skin disease cutaneous leishmaniasis (CL). Little is known about its tissue distribution and pharmacodynamics to inform clinical use in CL. Here, we compared the skin pharmacokinetics of LAmB with Fungizone® (DAmB), the deoxycholate form of AmB, in murine models of Leishmania major CL. Drug levels at the target site (the localized lesion) 48 hours after single intravenous (IV) dosing of the individual AmB formulations (1 mg/kg of body weight) were similar, but were 3-fold higher for LAmB than for DAmB on day 10 after multiple administrations (1 mg/kg on days 0, 2, 4, 6 and 8). After single and multiple dosing, intralesional concentrations were respectively 5- and 20-fold higher compared to those in the healthy control skin of the same infected mice. We then evaluated how drug levels in the lesion after LAmB treatment relate to therapeutic outcomes. After five administrations of the drug at 0, 6.25 or 12.5 mg/kg (IV), there was a clear correlation between dose level, intralesional AmB concentration and relative reduction in parasite load and lesion size (R2 values > 0.9). This study confirms the improved efficacy of the liposomal over the deoxycholate AmB formulation in experimental CL, which is related to higher intralesional drug accumulation.
| Type: | Article |
|---|---|
| Title: | Relation between Skin Pharmacokinetics and Efficacy in AmBisome Treatment of Murine Cutaneous Leishmaniasis |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1128/AAC.02009-17 |
| Publisher version: | http://dx.doi.org/10.1128/AAC.02009-17 |
| Language: | English |
| Additional information: | Copyright © 2017 Wijnant et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Pharmacokinetics, pharmacodynamics, amphotericin B, cutaneous leishmaniasis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10040882 |
Archive Staff Only
 |
View Item |
