Frauke Assmus (1,2), Supada Plitphonganphim (1,2), Richard M. Hoglund (1,2), Charles E. Mowbray (3), Stéphanie Braillard (3), Eric Chatelain (3), Louis Maes (4), Guy Caljon (4), Ivan Scandale (3), Joel Tarning (1,2)
(1) Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Thailand, (2) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom, (3) Drugs for Neglected Disease initiative, Switzerland, (4) Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Belgium
Introduction: Visceral leishmaniasis (kala-azar) is a neglected tropical disease caused by Leishmania parasites (L. donovani and L. infantum) and can be fatal if left untreated (1). Current therapies have severe limitations, such as cost, toxicity, resistance, and no oral formulation. Hence, there is an ongoing, high need for effective new treatment options (2). The novel benzoxaborole DNDi-6148 is a promising drug candidate for the treatment of visceral leishmaniasis (3) and has shown anti-leishmanial activity in vitro and in pre-clinical in vivo models (4). While DNDi-6148 has entered a Phase 1 clinical trial (5), information on the PK/PD relationship in pre-clinical species and appropriate PK/PD targets is limited.
Objectives: The aims of this study were i) to characterize the population pharmacokinetic properties of DNDi-6148 in mice and hamster and ii) to investigate the relationship between plasma exposure and anti-leishmanial activity in L.donovani and L.infantum-infected hamster and mice models.
Methods: Plasma concentration–time data for DNDi-6148 was available from non-infected Balb/c mice (n=38) and Golden Syrian hamsters (n=33). Animals received 6.25 – 50 mg/kg DNDi-6148 as oral gavage (single/multiple doses (5 days), once/twice daily). Satellite PK data for both species were analyzed using nonlinear mixed-effects modelling (NONMEM v 7.4). The final population pharmacokinetic models were used to simulate the various dosing scenarios investigated in infected mice and hamster. Anti-leishmanial activity was assessed in curative animal models following treatment on day 7 (mice) or day 10/21 (hamster) post-infection. Relative reduction of amastigotes in target tissues (liver, spleen, bone marrow) compared to vehicle-treated infected animals was used as a PD endpoint. The relationship between simulated drug exposure and anti-leishmanial activity was evaluated by linear and non-linear regression analysis in R (version 3.6). Models were compared on the basis of the Akaike and Bayesian information criterion (AIC, BIC) as well as goodness-of-fit diagnostics.
Results: DNDi-6148 pharmacokinetics in mice and hamster were well described by two-compartment disposition models with first order absorption. Higher dose was associated with a decrease in clearance (mice, hamster) and a decrease in relative bioavailability (mice). Body weight was implemented as an allometric function on clearance and volume parameters. The relationship between plasma exposure and reduction in amastigote burden was best described by an Emax (mice) and sigmoidal Emax model (hamster). Total plasma exposure (AUCinf ) was identified as the better predictor of anti-leishmanial activity as compared to peak plasma concentration (Cmax) or time > IC50 or > IC90, which was consistent across species.
Conclusions: In summary, exposure – response relationships for DNDi-6148 in Leishmania-infected mice and hamsters were successfully quantified. AUCinf was identified as a driver of anti-leishmanial activity. Our results provide a valuable tool to aid the dosing selection and design of prospective pre-clinical and clinical trials for visceral leishmaniasis drug discovery.
References:
[1] WHO World Health Organization. Leishmaniasis. 8 January 2022 (available from: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis).
[2] Alves F, Bilbe G, Blesson S, Goyal V, Monnerat S, Mowbray C, et al. Recent Development of Visceral Leishmaniasis Treatments: Successes, Pitfalls, and Perspectives. Clinical microbiology reviews. 2018;31(4).
[3] Mowbray CE, Braillard S, Glossop PA, Whitlock GA, Jacobs RT, Speake J, et al. DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis. Journal of medicinal chemistry. 2021;64(21):16159-76.
[4] Van Bocxlaer K, Caridha D, Black C, Vesely B, Leed S, Sciotti RJ, et al. Novel benzoxaborole, nitroimidazole and aminopyrazoles with activity against experimental cutaneous leishmaniasis. International journal for parasitology Drugs and drug resistance. 2019;11:129-38.
[5] Drug for Neglected Diseases initiative. Visceral leishmaniasis. DNDI-6148. 1 March 2022 (available from: https://dndi.org/research-development/portfolio/dndi-6148).
Reference: PAGE 30 (2022) Abstr 10186 [www.page-meeting.org/?abstract=10186]
Poster: Drug/Disease Modelling - Infection