A pharmacokinetic and pharmacodynamic study of artesunate for vivax malaria.

Abstract

Abstract. To investigate the pharmacokinetic and pharmacodynamic properties of artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) in Plasmodium vivax infections, 12 male Vietnamese adults with slide-positive vivax malaria received either intravenous ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2) with the alternative preparation given 8 hr later in a randomized, open, cross-over study. Following intravenous injection, ARTS had a peak plasma drug concentration (C max ) of 35.6 M (13.7 mg/L), an elimination half-life (t ½ ) of 2.2 min, a clearance (CL) of 3.0 L/hr/kg, and a volume of distribution (V) of 0.16 L/kg. Dihydroartemisinin had a C max of 7.7 M (2.2 mg/L), a t max of 8 min, a t ½ of 37 min, an apparent CL of 1.1 L/hr/kg, and an apparent V of 0.9 L/kg. Following oral ARTS, the mean relative bioavailability of DHA was 85%, the C max was 3.0 M (0.85 mg/L), the t max was 75 min, and t ½ was 40 min. The mean time to 50% reduction in the parasite count (PCT 50 ) and median fever clearance time were 3 hr and 16 hr, respectively. Following intravenous ARTS (group 1), the PCT 50 for total parasites, rings, trophozoites, and gametocytes was 3.3 hr, 3.2 hr, 4.0 hr, and 3.6 hr, respectively. This study confirms that ARTS is effective against P. vivax, with rapid clearance of sexual and asexual forms of the parasite. Artesunate is a suitable initial treatment for vivax malaria, or when the plasmodial species cannot be reliably identified.Artemisinin derivatives are often used first-line in the treatment of slide-positive falciparum malaria. Where microscopy is unavailable in the primary care setting or when there is doubt concerning the plasmodial species present in the blood film, artemisinin drugs can be given empirically. Preliminary evidence suggests that this practice is justifiable. Artemisinin is effective in the treatment of vivax malaria although, as in the case of falciparum malaria, recrudescence may occur. 1 Pharmacokinetic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) have been reported recently in Vietnamese children 2 and adults 3 with uncomplicated falciparum malaria. Studies in healthy volunteers 4,5 have shown that peak plasma concentrations of DHA are significantly lower. There is, therefore, a need to determine the pharmacokinetic properties of ARTS in vivax and other benign human malarias to ensure that relatively low drug concentrations do not result from administration of the recommended dosing regimens used in falciparum malaria, a situation that might contribute to high recrudescence rates.Pharmacodynamic studies of ARTS in falciparum malaria demonstrate rapid parasite clearance, 6 but are limited by the fact that only parasite forms in the first half of the life cycle are present in peripheral blood. All stages of development can be seen in vivax malaria. This provides an opportunity to assess the effects of antimalarial drugs across the 48-hr parasite life cycle.The aims of the present study were to obtain pharmacokinetic data for ARTS ...

Pharmacokinetic Profiles of Artesunate After Single Intravenous Doses at 0.5, 1, 2, 4, and 8 mg/kg in Healthy Volunteers: A Phase I Study

“…It is known that DHA has a longer half-life of 1.15-2.37 hours, which is 7.12-to 12.68-fold longer than AS, which has a short half-life of 0.12-0.24 hours. Therefore, the effectiveness of AS has been attributed to its rapid and extensive hydrolysis to DHA 5,7,32 and also to AS itself with a high initial C max . 23,24 In this study, the pharmacokinetics and possible side effects of an intravenous infusion of AS were studied in healthy volunteers.…”

“…4 The effectiveness of AS has been mostly attributed to its rapid and extensive hydrolysis to DHA. [5][6][7][8] Artemisinins have been used in malaria treatments with monotherapy regimen since 1983. However, the monotherapy with the artemisinin derivatives was significantly discouraged after 2001 to prevent the emergence of resistance.…”

Assessing drug sensitivity of Plasmodium vivax to halofantrine or choroquine in southern, central Vietnam using an extended 28-day in vivo test and polymerase chain reaction genotyping.

“…In Vietnam, artemisinin 34 and artesunate combined with mefloquine 35 have been used to treat vivax malaria. These drugs produced very rapid fever and parasite clearance times but recurrent parasitemia occurred in some patients treated with shorter courses of artemisinin-an inherent problem with this class of antimalarial drug.…”

Pharmacokinetics and Pharmacodynamics of Intravenous Artesunate in Severe Falciparum Malaria

“…The pharmacokinetics and pharmacodynamics of ARTS and other artemisinin derivatives have been assessed in patients with uncomplicated malaria (3,6,7,9), but there have been no equivalent studies with patients with severe Plasmodium falciparum infections. The dosing regimens used for patients with complications remain empirical and do not differ significantly from those used for patients with milder malaria (16,22,38).…”