Population Pharmacokinetics of Artesunate and Dihydroartemisinin following Intra-Rectal Dosing of Artesunate in Malaria Patients

Abstract

BackgroundIntra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria.Methods and FindingsAdults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36–1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0–6h were observed.ConclusionsThe pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations.

Pharmacokinetic and Pharmacodynamic Characteristics of a New Pediatric Formulation of Artemether-Lumefantrine in African Children with Uncomplicated Plasmodium falciparum Malaria

“…Analogous results have been reported for artesunate, another artemisinin derivative (23), where no significant relationships could be shown between parasite clearance and initial plasma concentrations of DHA or artesunate-DHA exposure (using AUC in the first 6 h). A semimechanistic model of parasite dynamics describing the early effect of artemether and DHA concentrations on the parasite density in malaria patients has recently been proposed (10).…”

Pharmacokinetics of dihydroartemisinin in Artekin tablets for single and repeated dosing in Chinese healthy volunteers

“…This means that gender did not affect or change the absorption, distribution and elimination of DHA in the human body. However, Simpson et al [19] suggested that the pharmacokinetic properties of DHA were affected only by gender and body weight in malarial patients. It may be caused by a different metabolism in healthy volunteers and malarial patients.…”

“…Xing et al [18] investigated the pharmacokinetic profile of b-DHA in rats after oral administration of 10 mg/ kg b-DHA and the mean values of C max and t max of DHA were 142.2 mg/l and 0.8 h, respectively. Simpson et al [19] studied the population pharmacokinetics of artesunate and DHA in malarial patients. They reported that the estimated elimination half-life of DHA was 43 min and the pharmacokinetic properties of DHA were affected only by gender and body weight.…”

Pharmacokinetics of Artemether-Lumefantrine and Artesunate-Amodiaquine in Children in Kampala, Uganda

“…The level of exposure to DHA was similarly higher in our children than in the healthy adults in our previous study (AUC 0-ϱ s, 382 and 198 ng ⅐ h/ml, respectively). Comparison of the PK data generated with patients to the data generated with healthy adults is a limitation, in that acute malaria alone may affect the disposition of artemisinin drugs (29). A strength of our comparison, however, is that the pediatric and adult studies used identical study designs.…”