Thomas P. C. Dorlo (1,2,3), Suman Rijal (4), Bart Ostyn (5), Peter J. de Vries (3), Rupa Singh (4), Narayan Bhattarai (4), Surendra Uranw (4), Jean-Claude Dujardin (5), Marleen Boelaert (5), Jos H. Beijnen (1,2), Alwin D.R. Huitema (1)
(1) Department of Pharmacy & Pharmacology, Slotervaart Hospital / the Netherlands Cancer Institute, Amsterdam, the Netherlands, (2) Division of Pharmacoepidemiology & Clinical Pharmacology, UIPS, Utrecht University, Utrecht, the Netherlands, (3) Div. Infectious Diseases, Academic Medical Center, Amsterdam, the Netherlands, (4) B.P. Koirala Institute for Health Sciences, Dharan, Nepal, (5) Institute of Tropical Medicine, Antwerp, Belgium
Objectives: Recent reports indicated high miltefosine treatment failure rates for the neglected tropical disease visceral leishmaniasis (VL) on the Indian subcontinent [1]. To further explore the pharmacological factors associated with these treatment failures, a population pharmacokinetic-pharmacodynamic (PK-PD) study was performed to examine the relationship between miltefosine drug exposure and treatment failure in a cohort of Nepalese VL patients treated with miltefosine monotherapy according to standard treatment protocols.
Methods: Sparse blood samples were collected nominally at the end of treatment (EOT) and the miltefosine steady-state concentrations in these samples were analyzed using liquid chromatography coupled to tandem mass spectrometry. A population PK-PD analysis was performed in a sequential manner using non-linear mixed-effects modeling (NONMEM 7.2) and a logistic regression model for the binary treatment outcome (failure vs. cure). A population pharmacokinetic model for miltefosine was developed [2,3] and used to derive several measures of individual drug exposure, linked to in vitro drug susceptibility of clinical Leishmania isolates from this Nepalese cohort (CEOT, AUC0-EOT, AUC0-∞, Time>EC50, Time>10xEC50).
Results: The overall probability of treatment failure was 21%. The time the plasma concentration exceeded 10x the EC50 of miltefosine (median 30.2 days) was significantly associated with treatment success and failure: the odds ratio for treatment failure increased with 1.08 (95% CI 1.01-1.17) for every day that the EOT blood concentration did not exceed 10xEC50.
Conclusions: We here established that achieving sufficient miltefosine exposure is a significant and critical factor for VL treatment success, which urges the evaluation of the recently proposed optimal allometric miltefosine dosing regimen [3]. This study constitutes a first step towards the definition of PK-PD targets to be attained for miltefosine in the treatment of VL.
References:
[1] Rijal et al. Clin Infect Dis. 2013; in press.
[2] Dorlo et al. Antimicrob Agents Chemother. 2008; 52:2855-60
[3] Dorlo et al. Antimicrob Agents Chemother. 2012; 56: 3864-72
Reference: PAGE 22 (2013) Abstr 2787 [www.page-meeting.org/?abstract=2787]
Poster: Infection