A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria

Abstract

Aims To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.v. and oral administration of ARTS to patients with acute, uncomplicated falciparum malaria. Methods Twenty-six Vietnamese patients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the alternative preparation given 8 h later in an open crossover design. Mefloquine (750 mg) was administered at 24 h. Plasma concentrations of ARTS and DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters were calculated by non-compartmental methods. The time to 50% parasite clearance (PCT 50 ) was calculated by linear interpolation of parasite density determinations. Linear least squares and multiple linear regression analyses were used to evaluate pharmacokineticpharmacodynamic relationships. Results Following i.v. bolus, ARTS had a peak concentration of 29.5 mm (11 mg l −1 ), elimination t 1/2 =2.7 min, CL=2.33 l h −1 kg −1 and V=0.14 l kg −1 .The C max for DHA was 9.3 mm (2.64 mg l . Following oral ARTS, relative bioavailability of DHA was 82%, C max was 2.6 mm (0.74 mg l −1 ), t 1/2 =39 min, and MAT=67 min. Overall, the PCT 50 and fever clearance time (FCT) were 6.5 h and 24 h, respectively. There was no correlation between PCT 50 or FCT and AUC, C max or MRT for DHA. Conclusions Despite rapid clearance of ARTS and DHA in patients with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA following oral ARTS administration, and clinical outcomes comparable with those after i.v. ARTS, support the use of the oral formulation in the primary care setting.

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

“…The most reasonable choice seems to be the use of dihydroartemisinin for in vitro assays since this derivative is relatively stable and all currently used artemisinin derivatives and those that are under advanced phases of development are rapidly transformed into dihydroartemisinin in humans. [14][15][16][17] The significant positive correlation between the in vitro responses to chloroquine and monodesethylamodiaquine or quinine and between the response to mefloquine and halofantrine is in agreement with in vivo resistance to amodiaquine, quinine, and halofantrine observed in Southeast Asia where a high level of resistance to chloroquine and mefloquine has emerged. 41,42 Cross-resistance between pyrimethamine and cycloguanil has also been observed in vitro and in vivo.…”

“…[10][11][12][13] Although pharmacokinetic data are incomplete, it has been established that all currently available artemisinin derivatives are metabolized rapidly to dihydroartemisinin, the biologically active main human metabolite. [14][15][16][17] In the case of sodium artesunate, the aqueous solution that is reconstituted by dissolving the anhydrous powder of the drug in 5% dextrose solution just before parenteral administration is known to hydrolyze the compound rapidly into dihydroartemisinin. 18 Initial in vitro studies on laboratory-adapted clones of P. falciparum have shown that dihydroartemisinin is more active than the other artemisinin derivatives.…”

Penetration of Dihydroartemisinin into Cerebrospinal Fluid after Administration of Intravenous Artesunate in Severe Falciparum Malaria

“…Assay of DHA in CSF was done by gas chromatography-mass spectrometry (15). For plasma assays, the relative standard deviations [RSDs] have been published (2,3), while RSDs between runs were Յ11% over the ranges of artesunate and DHA concentrations found in our patients. The limits of detection were 80 nmol/liter for artesunate and 70 nmol/liter for DHA.…”

“…This concentration, 0.11 Ϯ 0.02 mol/liter (mean Ϯ standard error of the mean; n ϭ 12), is only 10% of that required to inhibit neurite outgrowth in vitro, 1 mol/liter (21). We did not sample beyond 120 min, as concentrations of DHA in plasma after intravenous administration of artesunate are very low at this time (3,7). By contrast, the CSF concentration-time profile suggests that DHA could persist in CSF beyond 120 min.…”

Evaluation of efficacy and safety of artesunate and its active metabolite, dihydroartemisinin, in streptozotocin-induced diabetes rats by blood pharmacokinetic analysis

“…Many studies have investigated pharmacokinetic modeling for AS and DHA: non-, one-, and two-compartment and parent-metabolite simultaneous modeling [23][24][25][26]. The parent-metabolite (AS-DHA) simultaneous modeling was also applied in this study, but failed to fit the data or stabilize the parameters because the conversion of AS to DHA after its intravenous administration was too fast to accurately evaluate the conversion rate, namely the absorption rate constant (ka) of DHA; therefore, the pharmacokinetic analysis of AS and DHA were performed separately.…”