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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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. 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 (Engelska)Ingår i: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, nr 7, s. 1892-1898Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2016. Vol. 71, nr 7, s. 1892-1898
Nationell ämneskategori
Infektionsmedicin Farmaceutiska vetenskaper
Identifikatorer
URN: urn:nbn:se:uu:diva-308279DOI: 10.1093/jac/dkw089ISI: 000383246000019PubMedID: 27084920OAI: oai:DiVA.org:uu-308279DiVA: diva2:1049282
Tillgänglig från: 2016-11-24 Skapad: 2016-11-24 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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Dorlo, Thomas P. C.
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Institutionen för farmaceutisk biovetenskap
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