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Pharmacokinetics and pharmacodynamics of oleylphosphocholine in a hamster model of visceral leishmaniasis
Dafra Pharma Res & Dev, Slachthuisstr 30-7, Turnhout, Belgium.;McGill Univ, Dept Biochem, 1650 Cedar Ave, Montreal, PQ, Canada..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Univ Utrecht, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands..ORCID iD: 0000-0003-3076-8435
Univ Antwerp, Lab Microbiol Parasitol & Hyg LMPH, Univ Pl 1, Antwerp, Belgium..
Univ Antwerp, Lab Microbiol Parasitol & Hyg LMPH, Univ Pl 1, Antwerp, Belgium..
2016 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 7, 1892-1898 p.Article in journal (Refereed) Published
Abstract [en]

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 t(1/2) of similar to 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 similar to 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 (AUC(t-infinity)) correlates well with the prophylactic and curative efficacy of OlPC in the L. infantum hamster model.

Place, publisher, year, edition, pages
2016. Vol. 71, no 7, 1892-1898 p.
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Infectious Medicine Pharmaceutical Sciences
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URN: urn:nbn:se:uu:diva-308279DOI: 10.1093/jac/dkw089ISI: 000383246000019PubMedID: 27084920OAI: oai:DiVA.org:uu-308279DiVA: diva2:1049282
Available from: 2016-11-24 Created: 2016-11-24 Last updated: 2016-11-24Bibliographically approved

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Dorlo, Thomas P. C.
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