Tolerability and pharmacokinetics of non-fixed and fixed combinations of artesunate and amodiaquine in Malaysian healthy normal volunteers.
OBJECTIVE
There is limited pharmacokinetic data available for the combination artesunate + amodiaquine, which is used widely to treat uncomplicated malaria. This study examines the bioavailability and tolerability of a fixed (200 mg artesunate + 540 mg amodiaquine) and loose (200 mg + 612 mg) combination with a 2x2 cross-over design in 24 healthy volunteers.


METHODS
Parent compounds and metabolites [dihydroartemisinin (DHA) and desethylamodiaquine (DEAQ)] were measured by high-performance liquid chromatography-electrochemical detection, and the area under the curve (AUC)(0-t) and C(max) were compared by an analysis of variance (ANOVA) based on geometric least square means using the Schuirmann two one-sided test.


RESULTS
The AUC(0-t) for total DHA and DEAQ were 1522 +/- 633 and 30021 +/- 14211 ng h/ml for the fixed products and 1688 +/- 767 and 40261 +/- 19824 ng h/ml (mean +/- standard deviation) for the loose products. The ANOVA showed no statistical differences except for sequence effect for DHA. The values obtained with the fixed product were within the 125% bioequivalent limits but extend below the 80% bioequivalence limits.


CONCLUSIONS
Both combinations were well tolerated and had comparable pharmacokinetic profiles; differences are unlikely to be clinically relevant.
Navaratnam
Visweswaran
V
National Center for Drug Research (CRD), Universiti Sains Malaysia (USM), 11800 Minden, Pulau Pinang, Penang, Malaysia.
Ramanathan
Surash
S
Wahab
Mohd Suhaimi Ab
MS
Siew Hua
Gan
G
Mansor
Sharif Mahsufi
SM
Kiechel
Jean-René
JR
Vaillant
Michel
M
Taylor
Walter R J
WR
Olliaro
Piero
P
D000328:Adult; D000655:Amodiaquine / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D000962:Antimalarials / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D037621:Artemisinins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000077332:Artesunate; D044466:Asian People / Q000706:statistics & numerical data; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood; D016009:Chi-Square Distribution; D018592:Cross-Over Studies; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008296:Malaysia; D008297:Male; D012016:Reference Values; D013997:Time Factors
D000962:Antimalarials; D037621:Artemisinins; D015415:Biomarkers; D004338:Drug Combinations; D000655:Amodiaquine; D000077332:Artesunate