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

Malaria Journal

Research

Duangsuda Siriyanonda¹  Amporn Limsalakpeth¹  Maneerat Rasameesoraj¹  Nitima Chanarat¹  Paktiya Teja-Isavadharm¹  R. Scott Miller²  David L. Saunders³  Natthasorn Komcharoen⁴  Montip Gettayacamin⁵  Peter J. Weina⁶ 

[1] Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, 10400, Bangkok, Thailand;Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, 10400, Bangkok, Thailand;Global Health Division, Bill & Melinda Gates Foundation, 250/830 Moo3, Bangpla Soi 18, Seattle, USA;Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, 10400, Bangkok, Thailand;US Army Medical Materiel Activity, Ft Detrick, 21702, Frederick, MD, USA;Department of Veterinary Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, 10400, Bangkok, Thailand;Department of Veterinary Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, 10400, Bangkok, Thailand;AAALAC International Southeast Asia Office, 10540, Bangpla, Bangplee, Samutprakarn, Thailand;Walter Reed Army Institute of Research, 503 Robert Grant Avenue, 20910, Silver Spring, MD, USA;Director Research Programs, Walter Reed National Military Medical Center, 20889, Bethesda, MD, USA;

关键词: Monkey malaria;    Artelinic;    Artelinate;    Artesunate;    Pharmacokinetics;    Pharmacodynamics;    Parasite clearance;   

DOI  :  10.1186/s12936-016-1456-6

 received in 2016-04-05, accepted in 2016-07-28,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsSplenectomized 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.ResultsThe 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 (r2 > 0.7, p ≤ 0.002). Lastly, following IV AL, there was a modest inverse correlation between PCt1/2 and Cmax (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.ConclusionThe 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.

【 授权许可】

CC BY   
© The Author(s) 2016

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