Long-acting intramuscular injections of ELQ-331, an antimalarial agent

Abstract

The overarching premise of this investigation is that injectable, long-acting antimalarial medication would encourage adherence to a dosage regimen for populations at risk of contracting the disease. To advance support for this goal, we have developed oil-based formulations of ELQ-331 (a prodrug of ELQ-300) that perform as long-acting, injectable chemoprophylactics with drug loading as high as 160 mg/ml of ELQ-331. In a pharmacokinetic study performed with rats, a single intramuscular injection of 12.14 mg/kg maintained higher plasma levels than the previously established minimum fully protective plasma concentration (33.25 ng/ml) of ELQ-300 for more than 4 weeks. The formulations were well tolerated by the rats and the tested dose produced no adverse reactions. We believe that by extending the length of time between subsequent injections, these injectable oil-based solutions of ELQ-331 can offer a more accessible, low-cost option for long-acting disease prevention and reduced transmission in malaria-endemic regions and may also be of use to travelers.

Keywords: Antimalarial; ELQ; Long-acting injectable chemoprophylactic (LAI-C); Oil-based intramuscular injection.

Figure 1.

(a) Texture analyzer equipped with a syringe test fixture. (b, c) Close up of the syringe test fixture. (d) Plunger-stopper break loose force (PBF), maximum force (Fmax), and dynamic glide force (DGF). (e) Total work. Refer to Table 3 for formulation composition. Values are reported as mean ± S.D.; n=3 measurements.

Figure 2.

(a) In vitro release testing arrangement. Cumulative percent release profiles of ELQ-331 oil-based solution formulations with the oil floating on release medium model. (b) Sesame oil formulations. (c) Cottonseed oil formulations. Refer to Table 3 for formulation composition. Values are reported as mean ± S.D., n=6.

Figure 3.

Plasma concentrations of ELQ-300 in rats, administered ELQ-331 IM at a dose of 12.14 mg/kg, IM (the dose is the equivalent of 10.00 mg/ml ELQ-300). Each data point represents the mean and S.D. of n = 3 rats. Formulation F: 60% sesame oil, 40% benzyl benzoate. formulation H: 50% sesame oil, 40% benzyl benzoate, 10% benzyl alcohol.The minimum fully effective protective plasma concentration (MEP₁₀₀) of ELQ-300 is shown as a dotted line.