Translational PKPD modeling framework to assess the predictive performance of a preclinical visceral leishmaniasis hamster model
Thomas P.C. Dorlo (1,2), Louis Maes (3), Mats O. Karlsson (1), Stéphanie Braillard (4), Charles Mowbray (4)
(1) Dept. Pharmaceutical Biosciences, Uppsala University, Sweden; (2) Div. Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, the Netherlands; (3) Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Belgium; (4) Drugs for Neglected Diseases initiative, Geneva, Switzerland
Objectives: Efficacy of novel compounds against the parasitic neglected tropical disease visceral leishmaniasis (VL) is typically assessed by reduction of splenic or hepatic intra-macrophageal Leishmania parasite burden in a Golden hamster infection model. Selection of adequate clinical dosing regimens based on these experiments is difficult, since the predictive value of this model remains unassessed. The aim of this study was to develop a translational framework to incorporate and model available preclinical PK and PD data of the oral antileishmanial drug miltefosine, derive appropriate PKPD targets, and assess their predictive performance by comparing PK target attainment in human VL patients.
Methods: First, a population PK model for miltefosine was developed on data from 36 healthy hamsters. Animals were treated with various single and multiple (5 day) p.o. dose regimens between 5 and 40 mg/kg/day. Subsequently concentration-time curves and secondary PK parameters for both free and total concentrations were simulated for L. infantum-infected hamsters in 2 early curative studies. PD endpoint in these studies was Leishman-Donovan Unit (LDU), which is representative for the total parasite burden, in liver and spleen of each animal at 14 days post-treatment. Exposure-response curves were fitted using 4-parameter log-logistic models. PK analyses and simulations were performed in NONMEM 7.3 and PKPD using the ‘drc’-package in R.
Results: Miltefosine PK in hamsters could be described using a 1 compartment model, with various non-linearities characterized. Exposure-response curves for various PK parameters (AUC0-14d, Time>IC50, etc.) for both total and free miltefosine were successfully fitted. Various PK targets corresponding with 50%, 95% and 99% reduction of the parasite burden were calculated for each PKPD relationship. The probability of PK target attainment in human patients, accounting for species differences in protein binding, were compared to clinical outcome. Free AUC0-14d associated with 99% LDU reduction in hamster corresponded best with the observed fraction of human patients reaching this target in relation to clinical outcome.
Conclusions: For the first time PKPD relationships were quantified in Leishmania-infected hamsters. The translational framework may be a valuable tool to establish the best preclinical model and targets for drug discovery for leishmaniasis and help in the design of future first-in-human clinical trials.