ELQ-331 as a prototype for extremely durable chemoprotection against malaria

Abstract

Background: The potential benefits of long-acting injectable chemoprotection (LAI-C) against malaria have been recently recognized, prompting a call for suitable candidate drugs to help meet this need. On the basis of its known pharmacodynamic and pharmacokinetic profiles after oral dosing, ELQ-331, a prodrug of the parasite mitochondrial electron transport inhibitor ELQ-300, was selected for study of pharmacokinetics and efficacy as LAI-C in mice.

Methods: Four trials were conducted in which mice were injected with a single intramuscular dose of ELQ-331 or other ELQ-300 prodrugs in sesame oil with 1.2% benzyl alcohol; the ELQ-300 content of the doses ranged from 2.5 to 30 mg/kg. Initial blood stage challenges with Plasmodium yoelii were used to establish the model, but the definitive study measure of efficacy was outcome after sporozoite challenge with a luciferase-expressing P. yoelii, assessed by whole-body live animal imaging. Snapshot determinations of plasma ELQ-300 concentration ([ELQ-300]) were made after all prodrug injections; after the highest dose of ELQ-331 (equivalent to 30 mg/kg ELQ-300), both [ELQ-331] and [ELQ-300] were measured at a series of timepoints from 6 h to 5½ months after injection.

Results: A single intramuscular injection of ELQ-331 outperformed four other ELQ-300 prodrugs and, at a dose equivalent to 30 mg/kg ELQ-300, protected mice against challenge with P. yoelii sporozoites for at least 4½ months. Pharmacokinetic evaluation revealed rapid and essentially complete conversion of ELQ-331 to ELQ-300, a rapidly achieved (< 6 h) and sustained (4-5 months) effective plasma ELQ-300 concentration, maximum ELQ-300 concentrations far below the estimated threshold for toxicity, and a distinctive ELQ-300 concentration versus time profile. Pharmacokinetic modeling indicates a high-capacity, slow-exchange tissue compartment which serves to accumulate and then slowly redistribute ELQ-300 into blood, and this property facilitates an extremely long period during which ELQ-300 concentration is sustained above a minimum fully-protective threshold (60-80 nM).

Conclusions: Extrapolation of these results to humans predicts that ELQ-331 should be capable of meeting and far-exceeding currently published duration-of-effect goals for anti-malarial LAI-C. Furthermore, the distinctive pharmacokinetic profile of ELQ-300 after treatment with ELQ-331 may facilitate durable protection and enable protection for far longer than 3 months. These findings suggest that ELQ-331 warrants consideration as a leading prototype for LAI-C.

Keywords: Chemoprevention; Chemoprotection; Intra-muscular; Long-acting; Malaria; Plasmodium; Prodrug; Prophylaxis.

Fig. 1

Summary of Trial 1 protocol and results. The timepoints for blood stage challenges, blood sampling for snapshot pharmacokinetic analysis, and sporozoite challenges are noted on the x-axis. The outcomes of efficacy trials are represented graphically as red = no protection and green = complete protection, and the proportion of challenged mice with each outcome is noted. The table insert summarizes the results of snapshot PK at the indicated timepoints

Fig. 2

Pharmacokinetics of ELQ-300 after IM injection of 30 mg/kg ELQ-331 in Trial 2. Main figure summarizes Trial 2 PK results in a log-linear plot of [ELQ-300] (mean ± SEM) vs time. Inset 1 shows detail of days 0–7 in an expanded linear–linear plot of [ELQ-331] and [ELQ-300] vs. time. Inset 2 shows a composite log-linear plot combining values from Trial 1 and Trial 2

Fig. 3

Results of 2-compartment model fit. a Linear–linear plot of observed mean [ELQ-300] values at each timepoint (+ symbols) and values predicted from the curve fit (line). Estimated model parameters are shown in the insert table. Central = apparent volume of the central compartment (L); Cl_Central = central compartment clearance (L/h); ka_Central = rate constant for absorption; peripheral = apparent volume of the tissue compartment; Q12 = intercompartmental clearance (L/h). b Indicators of model fit validity: correspondence of observed and predicted values, unbiased distribution of residuals

Fig. 4

Snapshot pharmacokinetics of ELQ-300 during Trial 3. Snapshot plasma [ELQ-300] values from Trial 3, comparing IM injections of 10 mg/kg ELQ-331 with two other ELQ-300 prodrugs. The log-linear graphical representation of [ELQ-300] vs. time and summary table both display mean [ELQ-300] ± SEM

Fig. 5

Snapshot pharmacokinetics of ELQ-300 during Trial 4. Snapshot plasma [ELQ-300] values from Trial 4, comparing IM injections of 2.5, 5, and 10 mg/kg ELQ-331. The log-linear graphical representation of [ELQ-300] vs. time and summary table both display mean [ELQ-300] ± SEM