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



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.



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.



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.
Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok, 10400, Thailand. paktiyat@gmail.com.
Paktiya
0000-0003-4529-1035
P
Teja-Isavadharm
Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok, 10400, Thailand.
Duangsuda
D
Siriyanonda
Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok, 10400, Thailand.
Maneerat
M
Rasameesoraj
Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok, 10400, Thailand.
Amporn
A
Limsalakpeth
Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok, 10400, Thailand.
Nitima
N
Chanarat
Department of Veterinary Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok, 10400, Thailand.
Natthasorn
N
Komcharoen
Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.|Director Research Programs, Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA.
Peter J
PJ
Weina
Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok, 10400, Thailand.|US Army Medical Materiel Activity, Ft Detrick, Frederick, MD, 21702, USA.
David L
DL
Saunders
Department of Veterinary Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok, 10400, Thailand.|AAALAC International Southeast Asia Office, Bangpla, Bangplee, Samutprakarn, 10540, Thailand.
Montip
M
Gettayacamin
Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok, 10400, Thailand.|Global Health Division, Bill & Melinda Gates Foundation, 250/830 Moo3, Bangpla Soi 18, Seattle, USA.
R
R
Scott Miller
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077332:Artesunate; D004195:Disease Models, Animal; D008253:Macaca mulatta; D008288:Malaria / Q000188:drug therapy*; D013156:Splenectomy; D016896:Treatment Outcome; D014481:United States
D000962:Antimalarials; D037621:Artemisinins; C062768:artelinic acid; D000077332:Artesunate
Artelinate; Artelinic; Artesunate; Monkey malaria; Parasite clearance; Pharmacodynamics; Pharmacokinetics