Comparative pharmacokinetics and pharmacodynamics of intravenous artelinate versus artesunate in uncomplicated Plasmodium coatneyi-infected rhesus monkey model

Background: The US Army designed artelinate/lysine salt (AL) to overcome the instability of sodium artesunate in aqueous solution (AS). To select the most efficacious artemisinin treatment, direct comparison was performed in an uncomplicated non-human primate malaria model. Methods: Splenectomized rhesus monkeys were inoculated with Plasmodium coatneyi and on day six, single equimolar loading dose of IV AL (11.8 mg kg^-1) or IV AS (8 mg kg^-1) were administered followed by 1/2 the first dose once daily for 2 more days. Blood smear were performed twice daily and the number of parasites were counted microscopically. Blood samples were obtained after the first dose within 6 h for pharmacokinetic (PK) and ex vivo pharmacodynamic evaluation by simultaneously measuring plasma drug concentration and anti-malarial activity against Plasmodium falciparum in vitro. Results: The anti-P. coatneyi in vivo activity of both compounds were comparable, but the ex vivo anti-P. falciparum potency of the IV AS regimen as administered was sevenfold higher than that of IV AL. Comparing in vivo pharmacodynamics of AL and AS, daily assessed parasite counts showed comparable 99 % parasite clearance times (PC99: 2.03, 1.84 day), parasite clearance rates (5.34, 4.13 per min) and clearance half-life (PCt_1/2: 7.79, 10.1 h). This study showed strong and significant inverse correlation between PCt_1/2 and t_1/2 of AS + DHA, and AUC_0-∞ of DHA, and correlated with V_z of AS (r² > 0.7, p ≤ 0.002). Lastly, following IV AL, there was a modest inverse correlation between PCt_1/2 and C_max (r² 0.6, p ≤ 0.04). Although all tested monkeys recrudesced subsequently, two died following AL regimen before parasite clearance. While the aetiology of those deaths could not be definitively determined, pathologic evidence favoured a sepsis-like syndrome and suggested that severe malaria was more likely than drug toxicity. Conclusion: The model demonstrated that both AS and DHA contributed to the anti-malarial activity of IV AS, while IV AL activity was largely restricted to the parent drug. Parasite clearance was strongly and linearly dependent on drug exposure for both artemisinin regimens. However, IV AS had higher ex vivo potency against P. falciparum, leading to an IND filing for GMP manufactured AS in the United States.