Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate-Amodiaquine and Artemisinin-Piperaquine in Healthy Volunteers for Preselection Malaria Therapy

Abstract

The pharmacokinetics (PK) and ex vivo activity (pharmacodynamics [PD]) of two artemisinin combination therapies (ACTs) (artemisinin-piperaquine [ARN-PPQ] [Artequick®] and artesunate-amodiaquine [ARS-AQ] [Coarsucam™]) in healthy Vietnamese volunteers were compared following 3-day courses of the ACTs for the preselection of the drugs for falciparum malaria therapy. For PK analysis, serial plasma samples were collected from two separate groups of 22 volunteers after ACT administration. Of these volunteers, ex vivo activity was assessed in plasma samples from seven volunteers who received both ACTs. The area under the concentration-time curve (AUC0-∞) was 3.6-fold higher for dihydroartemisinin (active metabolite of ARS) than that for ARN, whereas the AUC0-∞ of desethylamodiaquine (active metabolite of AQ) was 2.0-fold lower than that of PPQ. Based on the 50% inhibitory dilution values of the volunteers' plasma samples collected from 0.25 to 3 hours after the last dose, the ex vivo activity of ARS-AQ was 2.9- to 16.2-fold more potent than that of ARN-PPQ against the drug-sensitive D6 Plasmodium falciparum line. In addition, at 1.5, 4.0, and 24 hours after the last dose, the ex vivo activity of ARS-AQ was 20.8-, 3.5-, and 8.5-fold more potent than that of ARN-PPQ against the ARN-sensitive MRA1239 line. By contrast, at 1.5 hours, the ex vivo activity of ARS-AQ was 5.4-fold more active than that of ARN-PPQ but had similar activities at 4 and 24 hours against the ARN-resistant MRA1240 line. The PK-PD data suggest that ARS-AQ possesses superior antimalarial activity than that of ARN-PPQ and would be the preferred ACT for further in vivo efficacy testing in multidrug-resistant falciparum malaria areas.

Figures

Figure 1.

Mean (SD) artemisinin (ARN) (A) and piperaquine (PPQ) (B) concentration–time curves following the administration of ARN (125 mg)–PPQ base (750 mg) (Artequick) daily for 3 days in 22 healthy male Vietnamese volunteers.

Figure 2.

Mean (SD) artesunate (ARS) and dihydroartemisinin (A), and amodiaquine (AQ) and desethylamodiaquine (B) concentration–time curves following the administration of ARS (200 mg)–AQ (540 mg) (Coarsucam) daily for 3 days in 22 healthy male Vietnamese volunteers.

Figure 3.

Comparison of the mean (SEM) inhibitory dilution (ID50: number of dilutions of plasma sample that produces a 50% inhibition of hypoxanthine uptake into malaria parasites compared to drug-free plasma control samples) of plasma samples obtained from seven healthy Vietnamese volunteers who were administered on separate occasions a 3-day course of the artemisinin combination therapies (ACT) [artesunate-amodiaquine (Coarsucam) or artemisinin-piperaquine (Artequick)] against the drug-sensitive D6 Plasmodium falciparum line. The difference between the two treatments is statistically significant P < 0.05 for the time points from 48.25 to 51 hours (inclusive) and not statistically significant for all other time points.