Bioavailability of a Co-formulated Combination of Amodiaquine and Artesunate under Fed and Fasted Conditions

Abstract

To assess the effect of food on the pharmacokinetics of the anti-malarial amodiaquine (AQ, CAS 6398-98-7) and artesunate (AS, CAS 182824-33-5) and their active metabolites [desethylamodiaquine (DSA, CAS 81496-81-3) and dihydroartemisinin (DHA, CAS79352-78-6), respectively] in healthy volunteers. In an open, two-way crossover study, 22 healthy male volunteers fasted overnight and were randomised to receive a single oral administration of 4 tablets of a fixed-dose combination containing 135 mg AQ and 50 mg AS in the absence or presence of a standardised high-fat breakfast, administered 30 min before drug administration. Blood samples were collected up to Day 10 and AQ, DSA, AS and DHA were assayed by an LC/MS/MS method. Relative to the fasting state, the administration of the fixed-dose combination after a high-fat breakfast resulted in delayed median Tmax values for AQ (15 min and for DSA (2.3 h). The geometric mean ratios (GMR) of fed to fasting conditions indicated increased Cmax values for AQ (GMR 1.22) (90% CI: 1.07-1.39) and DSA (GMR 1.21) (90% CI: 1.05-1.39) and increased AUC0-t values for AQ (GMR 1.59) (90% CI: 1.39-1.83) and for DSA (GMR 1.13) (90% CI: 1.04-1.24). The median Tmax values were not delayed for AS as opposed to DHA (approximately 1 h delay). The Cmax values were decreased for AS (GMR 0.36) (90% CI: 0.30-0.47) and for DHA (GMR 0.51) (90% CI: 0.44-0.60). The AUC0-t values were slightly decreased for AS (GMR 0.89) (90% CI: 0.74-1.06) and for DHA (GMR 0.93) (90% CI: 0.84-1.02). Intake of AQ and AS with a high fat meal resulted in (1) a statistically significant increase in blood levels of AQ and DSA which may affect the safety and tolerability of the study drugs and (2) a decrease in AS and DHA blood levels which may affect efficacy. These results suggest that the fixed-dose combination should not be administered with a high-fat meal.