Antimalarial Bioavailability and Disposition of Artesunate in Acute Falciparum Malaria

Abstract

The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated Plasmodium falciparum malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimalarial agent in patients with acute malaria was 61% (95% confidence interval [CI], 52 to 70%). The absorption and elimination of oral artesunate were rapid, with a mean elimination half-life of antimalarial activity of 43 min (95% CI, 33 to 53 min). Following oral administration to patients with acute falciparum malaria, peak antimalarial activity in plasma and the area under the plasma concentration-time curve were approximately double those during convalescence and the apparent volume of distribution and clearance were approximately half those during convalescence (P < 0.005). Acute malaria is associated with a significant reduction in the clearance of artesunateassociated antimalarial activity.Artemisinin (qinghaosu) and its derivatives are a major advance in antimalarial treatment (8). These drugs are increasingly used in southeast Asia for the treatment of multidrugresistant Plasmodium falciparum malaria (2,8,15,22). Artesunate, the most widely available of the artemisinin-related compounds, is a hemisuccinate derivative of dihydroartemisinin (DHA). It may be given parenterally, intravenously, intramuscularly, orally, or rectally. Oral artesunate is used either alone or in combination, usually with mefloquine (15). Despite considerable use in areas where malaria is endemic, there are relatively few data on the pharmacokinetics of artesunate in the treatment of malaria (2-4, 6, 9, 13, 21, 27). There are concerns that the various artesunate formulations may have different bioavailabilities and that the development of resistance will be accelerated if suboptimal doses are used (13,24). Optimization of dosing recommendations is also important because of evidence that high doses of parenteral artemisinin derivatives (artemether, arteether) are neurotoxic in experimental mammals (16).Oral artesunate and artemether, but not artemisinin, are hydrolyzed rapidly back to the common metabolite DHA, which is intrinsically more active as an antimalarial agent. Oral artesunate may be considered mainly a prodrug for DHA, as the metabolite is the main contributor to overall antimalarial activity (2, 6). Thus, in order to compare different formulations of these drugs accurately and to guide the accurate choice of compound, the bioavailability of the antimalarial agent must be assessed.Chemical methods for the assay of DHA and the related derivatives have a limit of accurate quantitation above the range of concentrations which provide significant antimalarial effect. High-performance liquid chromatography (HPLC) with electrochemical detect...

Pharmaceutical Equivalence of Some Commercial Samples of Artesunate and Amodiaquine Tablets Sold in Southwestern Nigeria

“…Magnus et al [14] stated in a previous study that counterfeit or substandard artemisinin-based derivatives were being sold in parts of Africa, presenting a potential route for resistance development in the future. Also in Cambodia in 1990, substandard antimalarials were reported as responsible for the deaths of at least 30 people [15]. The results from this work are the first to show, to the best of our knowledge, the circulation of substandard artesunate tablet in Nigeria.…”

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

“…By the addition of a hemisuccinate group, artesunate is more water-soluble with greater bioavailability and better pharmacological profile (Newton et al 2000). Apart from its effective anti-malarial actions, artesunate has promising anti-inflammatory potential in animal models of rheumatoid arthritis (Mirshafiey et al 2006;Li et al 2013), systemic lupus erythematosus (Jin et al 2009) and bacteria-induced sepsis (Li et al 2010;Jiang et al 2011).…”

Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin

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“…Its rapid hydrolysis into the more active metabolite means that although ARS may make a significant contribution to parasite kill [17], it is often referred to as a pro-drug for DHA [3], and some researchers take the viewpoint that it is therefore not necessary to model the parent drug. DHA is also rapidly eliminated, again either through activation by infected red blood cells or through further metabolism (e.g.…”

“…Even now in the 21st century, the most deadly strain Plasmodium falciparum infects 200 million people and causes over half a million deaths every year, with young children being most severely affected [2]. Artemisinin and its derivatives have been used as antimalarials with increasing frequency since the 1990s [3]. They are the most rapidly acting drugs out of the currently available anti-malarials [4], reducing the parasite biomass ∼10, 000-fold However, the behaviour of current artemisinins is still not fully understood; debate remains concerning their mechanism of action [7,8] and stage-specific effects [9].…”