Objective: The aim of the present study was to compare the pharmacokinetic properties, bioavailability and tolerability of artesunate (AS) and amodiaquine (AQ) administered as a fixed-dose combination (Amonate FDC tablets; Dafra Pharma, Turnhout, Belgium) or as a non-fixed dose combination of separate AS tablets (Arsuamoon; Guilin Pharmaceutical Co, Shanghai, China) and AQ tablets (Flavoquine; Sanofi-Aventis, Paris, France). Methods: This was a randomized, open label, two-period, two-treatment, two-sequence, cross-over study in which 60 healthy male Indian volunteers were given a single total oral dose of 100 mg AS and 400 mg AQ hydrochloride either as two tablets of Amonate FDC (AS 50 mg and AQ hydrochloride 200 mg) or as two AS tablets of the co-blister Arsuamoon (50 mg AS) together with two Flavoquine tablets (200 mg AQ hydrochloride). Plasma AS and blood AQ concentrations, as well as those of their respective active metabolites dihydroartemisinin (DHA) and desethylamodiaquine (DEAQ), were measured by high-performance liquid chromatography-tandem spectrometry. The pharmacokinetic parameters of AS, DHA, AQ and DEAQ were determined by non-compartmental analysis. Bioequivalence assessment was performed by analysis of variance (ANOVA), and calculation of the 90% confidence intervals of the geometric mean ratio test (fixed)/reference (non-fixed) for AUC0-t and Cmax for AS, AQ, DHA and DEAQ. Results: Interim analysis showed that both treatments were not bioequivalent; therefore, statistical analysis was carried out on the results of all subjects for whom blood/plasma concentrations were available for all four analytes (n = 26). The Cmax (maximum plasma/blood concentration) of AS was 67.0 ± 37.1 and 154.8 ± 116.2 ng/mL for the fixed-dose and non-fixed dose administration, respectively. The AUC0-t (area under the plasma concentration-time curve from time zero to the last measurable concentration) of AS was 60.1 ± 27.5 and 81.8 ± 44.3 ng h/mL for the fixed-dose and non-fixed dose administration, respectively. The 90% confidence intervals for Cmax and AUC 0-t of AS were outside the 80-125% acceptance range: 37.02-61.62% and 70.10-83.47%, respectively. The Cmax of AQ was 33.8 ± 13.6 and 31.4 ± 14.1 ng/mL for the fixed-dose and non-fixed dose administration, respectively. The AUC0-t of AQ was 332.3 ± 116.6 and 329.8 ± 99.5 ng h/mL for the fixed and non-fixed dose administration, respectively. For AQ, the 90% CIs for Cmax and AUC0-t were within the 80-125% acceptance range: 99.17-121.71 and 89.53-107.35%, respectively. Bioequivalence assessment based on the active metabolite data supported the bioequivalence conclusions based on the parent compound data. Both the fixed-dose and non-fixed dose administration of 100 mg AS and 400 mg AQ were well tolerated. Conclusion: Bioequivalence of the fixed-dose AS/AQ formulation with the non-fixed dose combination of the same drugs was not demonstrated for AS, but it was shown for AQ for both C max and AUC0-t. The results obtained on the active metabolites support this conclusion. Overall, the fixed-dose 50 mg AS/200 mg AQ tablets were not technically bioequivalent with 50 mg AS tablets and 200 mg AQ tablets administered separately. The difference cannot be explained by the pharmaceutical properties of the tablets and seems to be biologically related. © 2010 Springer-Verlag.
