Luka Verrest (1), Séverine Monnerat (2), Ahmed M. Musa (3), Jane Mbui (4), Eltahir AG Khalil (3), Joseph Olobo (5), Monique Wasunna (6), Alwin D.R. Huitema (1,7,8), Jos H. Beijnen (1), Henk D.F.H. Schallig (9), 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) Institute of Endemic Diseases, University of Khartoum, Sudan, (4) Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya, (5) Department of Medical Microbiology, College of Health Sciences, Makerere University, Kampala, Uganda, (6) Drugs for Neglected Diseases initiative (DNDi) Africa, Nairobi, Kenya, (7) Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, the Netherlands, (8) Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands, (9) Department of Medical Microbiology, Experimental Parasitology, Academic Medical Center, Amsterdam, the Netherlands
Introduction/Objectives: To achieve long-term cure of the neglected tropical parasitic infection visceral leishmaniasis (VL), sufficient parasite eradication 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 instrumental to identify risk factors for parasite recrudescence and the relationship with clinical relapse. Circulating Leishmania kinetoplast DNA (kDNA) in the blood could be suitable to characterise the kinetics of Leishmania parasites [1]. Longitudinal blood parasite loads in patients indicated different parasite profiles, i.e., partial or complete initial parasite clearance during treatment, and variable regrowth after treatment, in some cases later suppressed, presumably caused by the host’s immune system. Objectives of this modelling study were to characterise parasite clearance by different VL therapies, as well as parasite proliferation and subsequent parasite suppression after treatment. Moreover, we aim to evaluate haematological or parasitological markers associated with either parasite regrowth, parasite suppression, and clinical outcome.
Methods: Data originated from three clinical trials (NCT01067443[2], NCT02431143[3], NCT01980199) in which Eastern African VL patients received (1) liposomal amphotericin B followed by sodium stibogluconate (SSG) (11 days), (2) liposomal amphotericin B followed by miltefosine (11 days), (3) miltefosine (28 days), or (4) fexinidazole (10 days). Leishmania kDNA was quantified in whole blood with real-time quantitative PCR during and up to 6 months after treatment [1]. An integrated PK-PD model was developed using NONMEM (v 7.3). A turn-over model and exponential growth model were evaluated to describe parasite proliferation. PK-PD models of miltefosine [4] and fexinidazole and its active metabolites, and K-PD models of amphotericin B and SSG, were evaluated to induce drug-dependent killing of parasites. Direct and delayed sigmoidal Emax and linear models were evaluated to induce drug-dependent killing of parasites driven by individual predicted PK concentrations of the drugs, or recovery of the host’s immune response, driven by time after treatment. To allow for parasite recrudescence after complete drug-induced parasite depletion, the parasite compartment was restricted to ³1 parasite/mL. Different parasitological and haematological markers were evaluated by a covariate analysis for their effect on the extent of parasite regrowth after treatment, or the timing of parasite suppression after treatment. Besides, the association of model-based estimates with clinical outcome was evaluated.
Results: Parasite proliferation was best described by an exponential growth model, with an in vivo parasite doubling time of 7.8 days (11.2 RSE%). Drug-dependent parasite killing was best described by first-order linear models directly driven by the drug concentrations. Parasite growth was also suppressed by kimm, a first order elimination process described by a sigmoidal Emax function driven by time after treatment, representing the onset and magnitude of parasite suppression by the host’s immune system after start of treatment. Due to the highly variable parasite profiles, between-subject variability for some model parameters was high, i.e., >100 CV% for baseline parasite load, miltefosine and amphotericin B drug effects, and Emax and EC50 of kimm. Haematological and parasitological markers showed no or only a weak correlation with long-term clinical outcome, and their effect on parasite suppression after treatment could not be reliably quantified.
Conclusions: This is the first semi-mechanistic PK-PD model of Leishmania parasite kinetics in VL, which adequately described proliferation of Leishmania blood parasite loads in VL patients, parasite killing by different VL therapies, and suppression or recrudescence of the parasite after the end of treatment. This is also the first report of an estimate of in vivo parasite growth rate for visceral leishmaniasis. No haematological or parasitological markers could yet be identified to predict parasite response after the end of treatment. However, this semi-mechanistic model provides insight into the in vivo parasite growth rate and parasite clearance rates by different drugs.
References:
[1] Verrest, L et al. Clin. Infect. Dis. (2021) Advance online publication
[2] Wasunna, M et al. PLoS Negl Trop Dis (2016) 10(9): e0004880
[3] Mbui, J. et al. Clin. Infect. Dis. (2019) 68(9): 1530-1538
[4] Palic, S. et al. J Antimicrob Chemother (2020) 75: 3260-3268
Reference: PAGE 29 (2021) Abstr 9781 [www.page-meeting.org/?abstract=9781]
Poster: Drug/Disease Modelling - Infection