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

INTRODUCTION Oleylphosphocholine (OlPC) is in the same chemical class as miltefosine (MIL) and was shown to be of superior efficacy and safety at equivalent doses (Fortin et al. 2012; 2014). In the current study, the pharmacokinetic (PK) properties of OlPC were evaluated in hamsters following single oral dose administration. The prophylactic activity of the drug was also explored to establish exposure-activity relationships. Finally, based on knowledge gained on PK, the curative efficacy of a 2× 5 days administration of 20 mg/kg was tested in the context of a longer post-treatment evaluation period. METHODS Female golden hamsters (4-8/group) were administered single oral doses of 20, 50 and 100 mg/kg and blood samples were collected after 2, 6, 24, 32, 72 and 168 h for analysis. For prophylactic studies hamsters (6-7/gr) were given a 100 mg/kg single-dose on day -7, -4, -1 or -4 h prior to infection. The animals were infected on day 0 with 2× 107amastigotes of L. infantum and parasitic burdens were measured in the liver, spleen and bone marrow on day 21. In the curative model, the animals (6/gr) were infected on day 0 and treatment started on day 21. OlPC and MIL were orally dosed at 20 mg/kg for 2× 5 days. Amastigote burdens were determined on day 42 (10 days post end of treatment, dpt) or day 72 (40 dpt). RESULTS OlPC had an elimination t1/2 of ∼l50 hrs and doseproportionality was seen between 20, 50 and 100 mg/kg. A onecompartment disposition model with first-order absorption and elimination fitted best the data. The prophylactic activity of OlPC was in agreement with respective drug exposures, showing dose-dependent residual activity. Interestingly, a 100 mg/kg single dose administered on - 4 day still reduced the overall parasitic burden by ∼l 50%. In the curative model, a ≥99% clearance of the infection was observed at 10 dpt in all OlPCtreated animals and remained the same at 40 dpt. For MIL, a good efficacy was measured at 10 dpt (98, >99 and 90% of reduction in liver, spleen and bone marrow), but the parasite loads had increased at 40 dpt (67, 99 and 79%, respectively), reflecting relapse of the infection and inferiority to OlPC. CONCLUSION This study reveals that total OlPC plasma exposure is a good predictor of the prophylactic and curative efficacy in the hamster VL model. Translated to human, these results suggest that the daily dosing of OlPC will be adjustable to avoid side effects while retaining maximum drug efficacy.