Rasmus Henninger (1), Katrien Van Bocxlaer (2), Wietse Schouten (3), Jadel Müller Kratz (4), Thomas P.C. Dorlo (1)
(1) Department of Pharmacy, Uppsala University, Uppsala, Sweden, (2) York Biomedical Research Institute, Hull York Medical School, University of York, York, UK, (3) Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands, (4) Drugs for Neglected Diseases initiative, DNDi, Rio de Janeiro, Brazil
Introduction: Cutaneous Leishmaniasis (CL) represents the most common disease manifestation of the neglected tropical disease leishmaniasis, caused by various species of the protozoan parasite genus Leishmania.[1] Despite potentially causing lifelong scarring, serious disability and social stigmatization, current treatment options are associated with severe limitations in terms of safety, efficacy and/or cost.[2] Consequently, there is an urgent need for new, safe and efficacious drug agents to combat CL. Drugs for Neglected Disease Initiative (DNDi) has identified two compounds, nitroimidazole DNDI-0690 and benzoxaborole DNDI-6148, as promising lead candidates, demonstrating excellent anti-leishmanial activity in various in vitro and in vivo CL models, but little is known about their distribution into the skin target site.
Objectives: The aim of this study was to characterize the murine plasma population pharmacokinetics (PPK) of two novel anti-leishmaniasis drug candidates, DNDI-0690 and DNDI-6148, and to explore target site exposure in the skin.
Methods: For both drugs, plasma PK data originated from a dose-response study, in which a total of 24 L. major infected BALB/c mice were included in each study, divided equally among four dosage groups (6.25 mg/kg, 12.5 mg/kg, 25 mg/kg, and 50 mg/kg) and orally administered DNDI-0690 (QD) and DNDI-6148 (BID) for 10 consecutive days. Plasma PK samples for DNDI-6148 were collected at 0.5, 1, 2, 4, 8, and 24 hours, and for DNDI-0690 at 0.5, 1, 2, 4, 8, 12, and 24 hours, on both day 1 and day 10. Infected and non-infected skin samples were collected 24 hours post-dose on day 10. The plasma PPK were characterized using an NLME approach performed with MonolixSuite2023R1 and NONMEM 7.5.
Results: The PPK of murine DNDI-6148 were best described by a 1-compartment disposition model with first-order absorption and a Michaelis-Menten type elimination. The population parameter estimates were absorption rate constant (ka) 2.46 hr-1 95% confidence interval [2.21, 2.73], volume of distribution (V/F) 0.0028 L [0.0026, 0.0031], maximum elimination rate (Vmax/F) 108.59 L/hr [97.30, 121.19] and Michaelis-Menten constant (Km) 13.2 mg/L [11.2, 15.6]. The murine PPK of DNDI-0690 were best described by a 1-compartment model, with dual first-order absorption and linear elimination. Population parameter estimates were ka1 2.34 hr-1 [1.86, 2.94], ka2 0.40 hr-1 [0.20, 0.78] with a difference in lag-time (∆tlag) on the two absorption rate constants of 3.32 hr [2.75, 4.02], ka2 0.40 hr-1 [0.20, 0.78] with a difference in lag-time (∆tlag) of 3.32 hr [2.75, 4.02], fraction of drug absorbed with the first absorption rate constant (F1) 0.60 [0.52, 0.67], clearance (Cl/F) 0.0020 L/hr [0.0016, 0.0024] and V/F 0.015 L [0.012, 0.020]. For both drugs, the higher dose groups were associated with a less than dose-proportional increase in exposure, best characterized by a dose-dependent decrease in relative bioavailability (Frel). This effect was likely due to saturable absorption in the gut or dissolution limitations at higher doses. For DNDI-6148, Frel of dose groups 25 mg/kg and 50 mg/kg were 0.75 [0.72, 0.78] and 0.67 [0.63, 0.71], respectively. For DNDI-0690, Frel was best described with a power function with an exponent of -0.44 [-0.58, -0.31]. Within the 10 days of treatment, the median percentage time for which plasma concentrations of DNDI-0690 stayed above the in vitro IC50 value (4.56 µM, [3]) was 54%, 79%, 100% and 100% for dose groups 6.25-50 mg/kg, respectively. For DNDI-6148, the median percentage time for which plasma concentrations stayed above the in vitro IC50 value (2.10 µM, [4]) was 58%, 59%, 96% and 100%. Drug penetration into skin tissue was best described using an effect compartment, where Rskin:pl was the penetration coefficient (ratio) between infected/non-infected skin and plasma, and kpl-skin was the rate of drug transfer from plasma to skin. For DNDI-6148, Rskin:pl was estimated at 0.54 [0.336, 0.74], indicating reduced penetration from plasma to skin. Rskin:pl were similar in both infected and non-infected skin, indicating equal distribution into diseased and non-diseased skin. DNDI-0690 penetrated skin to a lesser degree with a Rskin:pl estimate of 0.21 [0.17, 0.25] and 0.16 [0.13, 0.20] for infected and non-infected skin, respectively, suggestive of enhanced delivery to lesioned skin.
Conclusions: The plasma PPK of two novel anti-leishmaniasis drug candidates, DNDI-0690 and DNDI-6148, were successfully characterized in a murine infection model of CL, and skin exposure was explored. These results provide a valuable basis for subsequent skin target site characterization, PKPD modelling and, ultimately, prediction of a human efficacious dose.
References:
[1] Leishmaniasis (2024). https://www.who.int/news-room/fact-sheets/detail/leishmaniasis.
[2] Croft SL, Olliaro P. Leishmaniasis chemotherapy-challenges and opportunities. Clinical Microbiology and Infection. 2011;17(10):1478–83.
[3] Wijnant GJ, Croft SL, De La Flor R, Alavijeh M, Yardley V, Braillard S, et al. Pharmacokinetics and pharmacodynamics of the nitroimidazole DNDI-0690 in mouse models of cutaneous leishmaniasis. Antimicrob Agents Chemother. 2019;63(9).
[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. Int J Parasitol Drugs Drug Resist. 2019;11:129–38.
Reference: PAGE 32 (2024) Abstr 11192 [www.page-meeting.org/?abstract=11192]
Poster: Drug/Disease Modelling - Infection