Pharmacokinetics and pharmacodynamics of oleylphosphocholine in a hamster model of visceral leishmaniasis.

Abstract

OBJECTIVES:

This study evaluated the pharmacokinetic properties of oleylphosphocholine (OlPC) in hamsters following a single oral dose. Its prophylactic activity was tested to establish exposure-activity relationships, while a 5 + 5 day oral regimen at 20 mg/kg with long post-treatment follow-up was performed to assess its curative potential.

METHODS:

Single oral doses of 20, 50 and 100 mg/kg were administered for pharmacokinetic analysis while a 100 mg/kg single oral dose was given on day 7, 4 or 1, or 4 h prior to infection in the prophylactic efficacy study. The animals were infected on day 0 with Leishmania infantum and the resulting parasite burdens were measured in target organs on day 21. In the curative model, treatment started on day 21 post-infection at 20 mg/kg for 5 + 5 days and amastigote burdens were determined in target organs either on day 42 [10 days after the end of treatment (dpt)] or day 72 (40 dpt).

RESULTS:

OlPC showed elimination t1/2 of ∼50 h and dose-proportional exposure. The prophylactic action of OlPC was in agreement with model-simulated drug exposures, showing dose-dependent residual activity. Interestingly, the 100 mg/kg single dose administered 4 days before infection (day -4) still reduced the overall parasite burden by ∼50%. In the curative model, >99% clearance of infection was observed at 10 dpt in all OlPC-treated animals and remained so at 40 dpt.

CONCLUSIONS:

This study reveals that total plasma exposure (AUCt-∞) correlates well with the prophylactic and curative efficacy of OlPC in the L. infantum hamster model.

• Authors: Anny Fortin, Thomas P C Dorlo, Sarah Hendrickx, Louis Maes
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 71 Issue 7 Pg. 1892-8 (07 2016) ISSN: 1460-2091 [Electronic] England
• PMID: 27084920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Antiprotozoal Agents
• oleylphosphocholine
• Phosphorylcholine

Topics

• Administration, Oral
• Animals
• Antiprotozoal Agents (administration & dosage, pharmacokinetics, pharmacology)
• Area Under Curve
• Chemoprevention (methods)
• Disease Models, Animal
• Female
• Leishmania infantum (drug effects)
• Leishmaniasis, Visceral (drug therapy, prevention & control)
• Mesocricetus
• Phosphorylcholine (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
• Plasma (chemistry)