Population pharmacokinetics of artesunate and amodiaquine in African children.
BACKGROUND
Pharmacokinetic (PK) data on amodiaquine (AQ) and artesunate (AS) are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC) of artesunate and amodiaquine.


METHODS
A prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm) to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA) and desethylamodiaquine (DeAq), the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI) between the areas under the plasma concentration-time curves (AUC).


RESULTS
The two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138) for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range) elimination half-life of 9 (7 to 12) days. Efficacy was similar in the two treatments groups, with cure rates of 0.946 (95% CI: 0.840-0.982) in the AS+AQ group and 0.892 (95% CI: 0.787 - 0.947) in the AS/AQ group. Four out of five patients with PCR confirmed recrudescences received AQ doses < 10 mg/kg. Both regimens were well tolerated. No child developed severe, post treatment neutropaenia (<1,000/muL). There was no evidence of AQ dose related hepatotoxicity, but one patient developed an asymptomatic rise in liver enzymes that was resolving by Day-28.


CONCLUSIONS
The bioavailability of the co-formulated AS-AQ FDC was similar to that of the separate tablets for desethylamodiaquine, DHA and the total anti-malarial activity. These data support the use this new AS-AQ FDC in children with acute uncomplicated falciparum malaria.
Stepniewska
Kasia
K
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. kasia@tropmedres.ac
Taylor
Walter
W
Sirima
Sodiomon B
SB
Ouedraogo
Esperance B
EB
Ouedraogo
Alphonse
A
Gansané
Adama
A
Simpson
Julie A
JA
Morgan
Caroline C
CC
White
Nicholas J
NJ
Kiechel
Jean-René
JR
D000349:Africa; D000655:Amodiaquine / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D037621:Artemisinins / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000077332:Artesunate; D001682:Biological Availability; D001711:Biotransformation; D002675:Child, Preschool; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007223:Infant; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D010949:Plasma / Q000737:chemistry; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C515299:amodiaquine, artesunate drug combination; D000655:Amodiaquine; D000077332:Artesunate
Antimicrob Agents Chemother. 2000 Apr;44(4):972-7
10722499
Bull World Health Organ. 2004 Dec;82(12):935-9
15654408
Trop Med Int Health. 2005 Feb;10(2):121-38
15679555
J Pharmacokinet Pharmacodyn. 2007 Oct;34(5):669-86
17620000
Am J Trop Med Hyg. 1999 Jan;60(1):14-21
9988316
Br J Cancer. 1977 Jan;35(1):1-39
831755
Bull World Health Organ. 1999;77(8):624-40
10516785
Stat Med. 1998 Apr 30;17(8):873-90
9595617
Malar J. 2009 Mar 16;8:48
19291301
Trans R Soc Trop Med Hyg. 2000 Apr;94 Suppl 1:S1-90
11103309
Drug Metab Pharmacokinet. 2008;23(3):158-64
18574319
Br J Clin Pharmacol. 1990 Jun;29(6):695-701
2378788
PLoS Med. 2006 Nov;3(11):e444
17132053
Br J Clin Pharmacol. 2005 Mar;59(3):298-301
15752375
Br J Clin Pharmacol. 1998 Apr;45(4):347-54
9578181
Life Sci. 1985 Jan 7;36(1):53-62
3965841
Bull World Health Organ. 2006 Dec;84(12):956-64
17242831
Br J Clin Pharmacol. 1994 May;37(5):401-4
8054244