(T1530-06-38) Formulation of an Antimalarial Agent (ELQ-598) as a Sustained Release Injectable

Purpose: The aim was the development of a long acting injectable product for malaria chemoprophylaxis with a new Endochin-like Quinolone (ELQ) compound, ELQ 598.

Methods: Solubility studies were performed with a next generation ELQ compound (ELQ 598). ELQ 598 is a prodrug of ELQ 596.¹ The solubility of ELQ 598 in a few selected solvents [Cottonseed oil (CSO), Sesame oil (SO), benzyl alcohol(BA), benzyl benzoate, (BB)] and a mix of these solvents were determined using a high throughput solvent screen (HTSS). Manual solubility screening was performed with solvents selected from the HTSS data. In vitro Release studies were performed under sink conditions using an Oil Floating on Release Medium ² model. A High performance liquid chromatography (HPLC) method was used to analyze the samples. Two formulations (ELQ 598 in formulation vehicles composed of 50% SO or CSO, 40% BB, and 10 % BA were advanced to a long term (~ 3 months) Pharmacokinetic (PK) study in rats. The formulations tested in the rat PK study were selected based on the solubility, the in vitro release data and our experience with other ELQ compounds. The formulations were administered intramuscularly. Plasma samples from the PK study were analyzed with a LC-MS/MS bioanalytical method. An internal standard was used. The lower limit of quantification was  1 ng/ml for ELQ 598 and 5 ng/ml for ELQ 596. Plasma drug level data was analyzed using Phoenix WinNonlin^® by non-compartmental approaches.

Results: ELQ 598 was found to be much more crystalline than other ELQs tested. Among the solvent combinations quite a few (combinations with a relative solubility of ELQ 598 less than ~ 0.2 in the HTSS) showed promise as potential long acting formulations for ELQ 598. These combinations are shown in Figure 1 (a).  In manual solubility studies it was determined that the solubility of ELQ 598 in an oil vehicle composed of 50% SO , 40% BB and 10% BA was ~ 32 mg/ml. In an alternate vehicle, where the SO was replaced with CSO, the solubility was ~ 86 mg/ml. A cumulative release of ~ 2.2 % was obtained at the end of 4 weeks from the in vitro dissolution tests. In the rat study, the PK parameters were similar between the two formulations used. Plasma levels are provided in Figure 1 (b). Drug levels were high ( > 10 ng/ml) during the course of the study (~ 3 months).

Conclusion: The formulations of ELQ 598 were able to provide sustained release of the active for the duration of the study  (~ 3 months) in rats. Based on data that ELQ 598 is more potent than other ELQ compounds¹, it is likely that a low dose could be used for a longer duration of protection in humans.

References: 1. Pou, S et al., 3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance, ACS infectious diseases, 2024, 10(7), 2419–2442.
2. Karunakaran D. et al., Long-acting intramuscular injections of ELQ-331, an antimalarial agent. Eur J Pharm Sci., 2024 Jul 1;198:106795.

Acknowledgements: The authors thank SRI International staff who participated in the work. This project was supported with funds from the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development Program, with additional supplemental funding from VA Technology Transfer, Merit Review Grant award number i01 BX003312 (M.K.R.). Research reported in this publication was also supported by the US National Institutes of Health under award numbers R01AI100569 and R01AI141412 (M.K.R.) and by the US Department of Defense Peer Reviewed Medical Research Program (Log # PR181134) (M.K.R.).


Figure 1. (a) Relative solubility of ELQ 598 in solvent combinations, (b) Plasma levels of ELQ 598 and ELQ 596 from a PK study in rats