Pharmacokinetics of Artesunate following Oral and Rectal Administration in Healthy Sudanese Volunteers

Abstract

The aims of this study were to determine the pharmacokinetic parameters of a single dose of 200 mg oral and rectal artesunate in healthy volunteers, and to suggest a rational dosage regimen for rectal administration. The study design was a randomized open cross-over study of 12 healthy volunteers; the analytical method used was a reversed phase high performance liquid chromatography with post column derivatization and subsequent ultraviolet detection. Pharmacokinetic parameters were derived from the main metabolite alpha-dihydroartemisinin data due to the rapid disappearance of artesunate from the plasma. Dihydroartemisinin following oral administration of artesunate had a significantly higher AUC(0-infinity) (P<0.05 95% confidence interval (CI) -1168.73, -667.61 ng x h/mL(-1)) and Cmax (P<0.05; 95% CI -419.73, -171.44 ng/mL(-1)), and had shorter tmax (P<0.05; 95% CI -0.97, -0.10 h) than that following rectal artesunate. There was no statistically significant difference in the elimination half-life between both routes of administration (P>0.05; 95% CI -0.14, 0.53 h). The relative bioavailability of rectal artesunate was [mean (coefficient of variation %) 54.9 (24.8%) %]. On the basis of these data an 8 hourly dosing regimen per day with rectal artesunate is proposed.

Pharmacokinetics of Artesunate Alone and in Combination with Sulfadoxine/Pyrimethamine in Healthy Sudanese Volunteers

“…Artesunate is presumed to undergo marked first-pass effect; thus, the variability might be caused by differences in the extent of the enzyme activity among persons. 15 After AS alone or in combination with SP, it has also been observed that the C max and AUC values of DHA, in the present study, exceeded that of AS (Tables 1 and 2). …”

“…13 Previously, the main methods for their quantification were electrochemical detection with detection limits of approximately 10 ng/mL by using sample volumes of approximately 0.5-1 mL plasma or post-column derivatization with methanolic alkali and subsequent ultraviolet detection with limits of detection of approximately 30 ng/mL. [14][15][16][17][18][19][20] Currently, the suitable method for quantification of these compounds in plasma is liquid chromatography coupled with mass spectrometry detection (LC-Ms or LC-MS/MS) with quantification limits of approximately 1 ng/mL using only 50-μL plasma sample volumes. [21][22][23][24][25] However, some of the problems encountered the latter bioanalytical methods include lack of appropriate stable isotope-labeled AS and DHA internal standards, in addition to expensive solid phase extraction cartridges that most commonly used for extraction of AS and DHA from biological samples.…”

Descriptive Study on the Efficacy and Safety of Artesunate Suppository in Combination With Other Antimalarials in the Treatment of Severe Malaria in Sudan

“…Using pharmacokinetic data from healthy volunteers, an appropriate dose of artesunate was selected for administration per rectum that would be expected to provide blood levels of dihydroartemesinin above the minimum inhibitory concentration that eliminates 90% of the parasites (MIC 90 ) for 5.3 ± 2.1 hours. 10 The rapid parasite clearance and deffervescence of fever in all 99 patients confirms the dosing schedule in this group of patients was entirely appropriate. The parasitemia and fever clearance times in this study were significantly shorter than that reported by Looareesuwan et al 11,12 and Thwe et al 13 but not significantly different from that reported by Eduardo and Gomez 14 and Bhatt et al 15 The choice of second agent was made based on available data of mefloquine from Southeast Asia and cost because pyrimethamine/sulfadoxine and doxycycline are inexpensive and widely available.…”

“…Group C (30 patients): Mefloquine tablets (total dose, 15 mg/kg body weight), split in 2 equal doses 24 hours apart, started 12 hours after the last dose of artesunate A pharmacokinetic study of oral and rectally administered artesunate in Sudanese healthy volunteers was used to devise the suggested dosage regimen of rectal artesunate, 200-mg rectocaps every 8 hours. 10 Patients were laid in a left lateral position, and an artesunate rectocap was inserted into the rectum beyond the anal verge by a trained nurse. The patients were confined to bed for at least 1 hour after the insertion; if the rectocap was expelled within 1 hour of administration, another dose was inserted.…”

“…8 Rectal artesunate has been shown to be absorbed rapidly, with a considerable interindividual variability. 9,10 Artesunate is highly effective against multidrug-resistant falciparum malaria and severe malaria in Vietnam, Thailand, China, and Myanmar 7 ; however, limited studies have been carried out in Africa.…”