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 (PCt1/2: 7.79, 10.1 h). This study showed strong and significant inverse correlation between PCt1/2 and t1/2 of AS + DHA, and AUC0-∞ of DHA, and correlated with Vz of AS (r(2) > 0.7, p ≤ 0.002). Lastly, following IV AL, there was a modest inverse correlation between PCt1/2 and Cmax (r(2) 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.

Antibody profiles to plasmodium merozoite surface protein-1 in Cambodian adults during an active surveillance cohort with nested treatment study.

BACKGROUND: In addition to evidence for a protective role of antibodies to the malaria blood stage antigen merozoite surface protein 1 (MSP1), MSP1 antibodies are also considered as a marker of past malaria exposure in sero-epidemiological studies. METHODS: In order to better assess the potential use of MSP1 serology in malaria chemoprophylaxis trials in endemic areas, an analysis for the prevalence of antibodies to both Plasmodium falciparum and Plasmodium vivax MSP142 in healthy Cambodian adults was conducted at two sites as part of an active, observational cohort evaluating the efficacy of dihydroartemisinin-piperaquine (DP) for uncomplicated malaria (ClinicalTrials.gov identifier NCT01280162). RESULTS: Rates of baseline sero-positivity were high (59 and 73% for PfMSP142 and PvMSP142, respectively), and titers higher in those who lived in a higher transmission area, although there was little correlation in titers between the two species. Those volunteers who subsequently went on to develop malaria had higher baseline MSP142 titers than those who did not for both species. Titers to both antigens remained largely stable over the course of the 4-6 month study, except in those infected with P. falciparum who had multiple recurrences. CONCLUSION: These findings illuminate the difficulties in using MSP142 serology as either a screening criterion and/or biomarker of exposure in chemoprophylaxis studies. Further work remains to identify useful markers of malarial infection and/or immunity.