title: Pharmacokinetics and pharmacodynamics of oleylphosphocholine in a hamster model of visceral leishmaniasis.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.affiliation: Dafra Pharma Research & Development, Slachthuisstraat 30/7, Turnhout, Belgium McGill University, Department of Biochemistry, 1650 Cedar Ave, Montreal, Quebec, Canada anny.fortin@mcgill.ca.
authors.forename: Anny
authors.initials: A
authors.lastname: Fortin
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Thomas P C
authors.initials: TP
authors.lastname: Dorlo
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, Wilrijk-Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hendrickx
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, Wilrijk-Antwerp, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D018890:Chemoprevention / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D018314:Leishmania infantum / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000517:prevention & control*; D008647:Mesocricetus; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010949:Plasma / Q000737:chemistry
chemical_list: D000981:Antiprotozoal Agents; C000621969:oleylphosphocholine; D010767:Phosphorylcholine