This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (2)  • Contact me when this article is cited  Related Content  • Similar articles in JAMA  Topic Collections  • Review  • Malaria  • Drug Therapy, Other  • Alert me on articles by topic

Harin A. Karunajeewa, FRACP; Laurens Manning, MB,BS; Ivo Mueller, PhD; Kenneth F. Ilett, PhD; Timothy M. E. Davis, FRACP

JAMA. 2007;297:2381-2390.

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Reviews, Global Health, Web of Science, and CINAHL computerized databases up to December 2006, along with reviewing unpublished data from conference proceedings, pharmaceutical companies, and regulatory applications.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 (C_max), time to C_max (T_max), 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 T_max and higher C_max 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.

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).

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Artesunate for the Treatment of Severe Falciparum Malaria
Rosenthal
NEJM 2008;358:1829-1836.
FULL TEXT