Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration

Abstract

Artesunate (AS) is a clinically versatile artemisinin derivative utilized for the treatment of mild to severe malaria infection. Given the therapeutic significance of AS and the necessity of appropriate AS dosing, substantial research has been performed investigating the pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA). In this article, a comprehensive review is presented of AS clinical pharmacokinetics following administration of AS by the intravenous (IV), intramuscular (IM), oral or rectal routes. Intravenous AS is associated with high initial AS concentrations which subsequently decline rapidly, with typical AS half-life estimates of less than 15 minutes. AS clearance and volume estimates average 2 - 3 L/kg/hr and 0.1 - 0.3 L/kg, respectively. DHA concentrations peak within 25 minutes post-dose, and DHA is eliminated with a half-life of 30 - 60 minutes. DHA clearance and volume average between 0.5 - 1.5 L/kg/hr and 0.5 - 1.0 L/kg, respectively. Compared to IV administration, IM administration produces lower peaks, longer half-life values, and higher volumes of distribution for AS, as well as delayed peaks for DHA; other parameters are generally similar due to the high bioavailability, assessed by exposure to DHA, associated with IM AS administration (> 86%). Similarly high bioavailability of DHA (> 80%) is associated with oral administration. Following oral AS, peak AS concentrations (Cmax) are achieved within one hour, and AS is eliminated with a half-life of 20 - 45 minutes. DHA Cmax values are observed within two hours post-dose; DHA half-life values average 0.5 - 1.5 hours. AUC values reported for AS are often substantially lower than those reported for DHA following oral AS administration. Rectal AS administration yields pharmacokinetic results similar to those obtained from oral administration, with the exceptions of delayed AS Cmax and longer AS half-life. Drug interaction studies conducted with oral AS suggest that AS does not appreciably alter the pharmacokinetics of atovaquone/proguanil, chlorproguanil/dapsone, or sulphadoxine/pyrimethamine, and mefloquine and pyronaridine do not alter the pharmacokinetics of DHA. Finally, there is evidence suggesting that the pharmacokinetics of AS and/or DHA following AS administration may be altered by pregnancy and by acute malaria infection, but further investigation would be required to define those alterations precisely.

A review of clinical pharmacokinetics of chloroquine and primaquine and their application in malaria treatment in Thai population

“…The observation of slight decrease in PQ clearance may have been due to the inhibition of CYP2D6 and/or CYP3A4. AS has a very short elimination half-life (approximately 1 h) as it is rapidly metabolized by esterase-catalyzed hydrolysis and hepatic CYP2A6 into DHA, which is subsequently metabolized by UGTs1A9 and 2B7 to glucuronide metabolites (Navaratnam et al, 2000;Morris et al, 2011). These results were consistent with the previous reports showing a similar interaction between PQ and CQ and also between PQ and PIP .…”

“…Adverse effects reported included nausea and elevated levels of direct and total bilirubin. The pharmacokinetics of all drugs were in close agreement with those previously reported (Navaratnam et al, 2000;Morris et al, 2011). The single oral dose of PQ did not result in any clinically relevant pharmacokinetic alterations to PYR, AS, or DHA exposures.…”

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

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

“…Artesunate (hereafter ARS) is the most frequently used artemisinin derivative, and is rapidly and almost entirely converted to dihydroartemisinin (hereafter DHA) in vivo, mostly by plasma esterases and liver cytochrome P450 CYP2A6 [12][13][14]. DHA is the most active of all artemisinin derivatives, with activity approximately 1.4 times that of ARS [15].…”

“…ARS is water soluble, facilitating its absorption [16] (usually assumed to be fast, efficient and first-order [12]). 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.…”