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June 6, 2007

Rectal Administration of Artemisinin Derivatives for the Treatment of Malaria

Author Affiliations

Author Affiliations: Medicine Unit, School of Medicine and Pharmacology, University of Western Australia, Fremantle, Australia (Drs Karunajeewa, Manning, and Davis); Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia (Dr Ilett); and Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea (Dr Mueller).

JAMA. 2007;297(21):2381-2390. doi:10.1001/jama.297.21.2381

Context Rectal administration of artemisinin derivatives is a potentially lifesaving emergency treatment of severe malaria. Many different preparations are marketed in tropical countries, but their pharmacokinetic disposition and clinical efficacy may vary.

Objective To review the pharmacokinetics, efficacy, and safety of rectally administered artesunate, artemisinin, dihydroartemisinin, and artemether.

Data Sources We searched the MEDLINE, EMBASE, Cochrane Database of Clinical Reviews, Global Health, Web of Science, and CINAHL computerized databases up to December 2006, along with reviewing unpublished data from conference proceedings, pharmaceutical companies, and regulatory applications. Studies in languages other than English were translated.

Study Selection Studies were included involving rectal administration of an artemisinin derivative to healthy volunteers or patients with measurement of plasma drug concentrations or rates of initial parasite clearance. Both single-arm and comparative trials were included.

Data Extraction Forty-five studies were identified, of which 39 eligible studies were included in the review. Primary efficacy outcome measures included parasite density as a percentage of baseline at 12 and 24 hours following the first dose. Pharmacokinetic variables included maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the plasma concentration–time curve. Weighted means were calculated from available data.

Data Synthesis Thirty-two studies provided valid clinical efficacy data: 19 of artesunate, 10 of artemisinin, 2 of dihydroartemisinin, and 1 of artemether. All demonstrated prompt parasite clearance, with evidence of a dose-dependent effect for artesunate. Mortality rates in severe malaria (weighted means, 0%-13%) were consistent with those expected. Eight studies compared rectal artemisinin with conventional parenteral treatment (quinine, artemether, or artesunate) for severe malaria. Despite similar clinical outcomes, rectal artemisinin derivatives initiated parasite clearance more rapidly than parenteral treatment (percentage of baseline at 12 hours, ≤27% vs ≥56%, respectively). Eighteen pharmacokinetic studies were identified, including 13 of artesunate. There was marked interindividual variability in most pharmacokinetic variables, but artesunate achieved an earlier Tmax and higher Cmax and area under the plasma concentration–time curve than other artemisinin derivatives.

Conclusions Available rectal preparations of artemisinin derivatives differ in their pharmacokinetic disposition. Most available evidence pertains to artesunate and artemisinin. Despite marked interindividual variability in bioavailability, rectal preparations appear to have acceptable therapeutic efficacy, including in severe illness.

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