Luka Verrest (1), Séverine Monnerat (2), Gerard J. Schoone (3), Alwin D.R. Huitema (1,4), Jos H. Beijnen (1), Henk D.F.H. Schallig (3), Fabiana Alves (2), Thomas P.C. Dorlo (1)
(1) Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, the Netherlands, (2) Drugs for Neglected Diseases initiative, Geneva, Switzerland, (3) Department of Medical Microbiology, Experimental Parasitology, Academic Medical Center, Amsterdam, the Netherlands, (4) Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, the Netherlands
Introduction/Objectives: In the search for better treatment regimens for the neglected tropical disease visceral leishmaniasis (VL), oral fexinidazole has been tested as a drug candidate in VL patients. However, the study was discontinued due to poor clinical response. To achieve long-term cure in VL patients, sufficient parasite depletion during treatment, as well as adequate suppression of parasite regrowth by the host’s immune system might be needed. A more detailed understanding of the parasite dynamics is needed to identify risk factors for parasite recrudescence and clinical relapse. Circulating Leishmania kinetoplast DNA (kDNA) could be suitable to characterise the kinetics of Leishmania parasites, where kDNA represents the parasite load and blood serves as a proxy compartment for the infected organs. Objectives of this study were to characterise 1) parasite depletion by fexinidazole, 2) parasite proliferation based on parasite recrudescence in relapsed patients, and 3) parasite suppression after treatment in cured patients.
Methods: Data originated from a Phase II clinical trial (NCT01980199) in which Sudanese VL patients received a flat dosing of 1800 mg/day fexinidazole for 4 days, followed by 1200 mg/day for 6 days. From 14 adult patients, whole blood concentrations of fexinidazole and its active metabolites fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2) were available from dried blood spot samples. These data were used to develop a population PK model previously, which could adequately describe the concentration-time course of fexinidazole, M1, and M2. Leishmania kDNA was quantified with real-time quantitative PCR (qPCR) in whole blood samples during and up to 6 months after treatment. An integrated PK-PD model was developed using NONMEM (v 7.3). The structural and stochastic PK parameters were fixed to the parameter values from the PK model. A turn-over model and exponential growth model were evaluated to describe parasite proliferation. Fexinidazole dose, AUC0-inf of M2, and predicted PK concentrations of M1 and M2 were evaluated to induce drug-dependent killing of parasites. Direct and delayed sigmoidal Emax and linear drug effects were evaluated. Different parasitological and haematological markers were evaluated to suppress parasite regrowth in cured patients.
Results: A decline in blood parasite load was observed in all patients, but only three out of 14 patients remained cured during the 6-month follow-up period. Parasite proliferation was best described by an exponential growth model, with an in vivo parasite doubling time of 7.8 days. Fexinidazole-dependent parasite killing was best described by a linear model directly driven by the summed concentrations of M1 and M2. Typical parameter values (%RSE) were a baseline parasite load of 3112 (5.1) parasites/mL, a Kgrowth of 0.0037 (13.1) h-1, and a slope of the M1+M2 concentration-effect relationship of 0.0009 mL/(µgM1+M2*h) (18.9). Between-subject variability was applied to baseline parasite load (154.9% (50.8)) and the slope (64.1% (76.7)). To accommodate for successful cure of patients, parasite growth was completely suppressed if the predicted parasite load reached <1 parasite/mL. Haematological markers showed a correlation with clinical outcome, but their effect could not be reliably quantified at this stage.
Conclusions: This semi-mechanistic PK-PD model could adequately describe the decline of Leishmania blood parasite loads in VL patients during treatment with fexinidazole, as well as recrudescence of the parasite in relapsing patients after the end of treatment. Suppression of parasite regrowth only accurately described one out of three cured patients. In order to improve the prediction in cured patients, we will add PD data from trials with different treatment regimens and higher cure rates.
Reference: PAGE () Abstr 9446 [www.page-meeting.org/?abstract=9446]
Poster: Drug/Disease Modelling - Infection