Flávia Teixeira 1, Pedro Silva 2, Thomas Dorlo 3, Sandra Haas 1
1 Pharmacology and Pharmacometric Laboratory, Federal University Of Pampa (Uruguaiana, Brazil), 2 Federal University Of Santa Maria (Santa Maria, Brazil), 3 Uppsala University (Uppsala, Sweden)
Background and objectives: Leishmaniasis is a zoonotic disease caused by the intracellular protozoan Leishmania sp., transmitted by phlebotomine vectors, affecting millions of individuals, predominantly those with limited economic resources. In Rio Grande do Sul, Brazil, the vector is present in urban areas; therefore, canines may be exposed and continue to propagate the disease, serving as reservoirs. Existing therapeutic options are associated with several adverse effects. Hence, novel molecules with leishmanicidal properties are under investigation. LASSBio-1736 (LB) was developed as a potential pharmacological agent for the treatment of Leishmaniasis and has demonstrated efficacy against the promastigote forms of L. major. At present, formulations are being developed to enhance the aqueous solubility and bioavailability of LB. This study aimed to characterize the pharmacokinetics of LB in rats.
Methods: Pharmacokinetic data from rats (n=10 per group) following intravenous and oral administration were incorporated into the analysis. For intravenous administration, rats received 3.2 mg/kg of pure LB. For oral administration, 12.6 mg/kg of pure LB or a suspension containing LB was administered (Ethical protocol: CEUA 027/23). Plasma concentrations were measured using LC-DAD, which had been previously validated [1-2]. Population pharmacokinetic (popPK) analyses were performed utilizing NONMEM 7.5. All estimations applied the first-order conditional estimation method with interaction (FOCE-I). PsN toolkit (Perl-speaks-NONMEM) version 5.6.0 was used for complementary analysis. Model management was done in PIRANA version 2.9.6 (Pirana Software and Consulting). Initially, a basic popPK model that included intravenous data was developed to characterize the typical concentration-time profile; subsequently, oral data were integrated into the model. Model selection was guided by (i) a significantly change in the value of the objective function (OFV), considering a decrease of 3.84, or 6.64 points in OFV (p < 0.05 or p < 0.01, respectively) for the evaluation of two models; (ii) visual exploration of goodness-of-fit (GOF) plots, and (iii) precision of model parameters reflected as the relative standard error (RSE%) computed as the ratio between the standard error and the parameter estimate.
Results: A total of 402 blood sample concentrations were available for analysis. A two-compartment model with first-order absorption and elimination more accurately described the LB pharmacokinetics. After adjustment and evaluation, the estimates (RSE) were: clearance (CL) = 21.6 mL/h (10%), central volume of distribution (V1) = 82.9 mL/kg (20%), peripheral volume of distribution (V2) = 243 mL/kg (15%), intercompartmental clearance (Q) = 27.6 mL/h (26%), absorption rate for pure LB = 0.0617 h-1 (28%), absorption rate for suspension LB = 0.114 h-1 (24%), available fraction for pure LB = 0.3 (16%), and available fraction for suspension LB = 0.515 (14%). Interindividual variability was observed in CL (0.0886), V1 (0.62), V2 (0.221), and Q (0.679).
Conclusion: The developed population pharmacokinetic model effectively characterized the observed data, indicating greater drug disposition when administered as a suspension than when administered as the pure molecule. The next step is to apply this model to dogs with leishmaniasis.
References:
[1] Moraes BS et al. (2018). Leishmanicidal candidate LASSBio-1736, a cysteine protease inhibitor with favorable pharmacokinetics: low clearance and good distribution.
[2] Moraes BS et al. (2016). Simple HPLC‐UV for the quantification of a new leishmanicidal candidate (E)‐1‐4(trifluoromethyl) benzylidene)‐5‐(2‐4‐dichlorozoyl) carbonylhydrazine (LASSBio‐1736) in rat plasma for pharmacokinetics assessment.
[3] Baxarias M et al. (2023). A blinded, randomized and controlled multicenter clinical trial to assess the efficacy and safety of Leisguard(®) as an immunotherapeutic treatment for healthy Leishmania infantum-seropositive dogs.
Reference: PAGE 34 (2026) Abstr 11927 [www.page-meeting.org/?abstract=11927]
Poster: Drug/Disease Modelling - Other Topics