Comparative Pharmacokinetics of Intramuscular Artesunate and Artemether in Patients with Severe Falciparum Malaria

ABSTRACT The first-dose pharmacokinetic properties of intramuscular (i.m.) artesunate (ARTS; 2.4 mg/kg immediately [stat], followed by 1.2 mg/kg i.m. daily) and artemether (ARM; 3.2 mg/kg i.m. stat, followed by 1.6 mg/kg i.m. daily) were compared in Vietnamese adults with severe falciparum malaria. A total of 19 patients were studied; 9 received ARTS, and 10 received ARM. ARTS was absorbed very rapidly; concentrations in plasma peaked between 1,362 and 8,388 nmol/liter (median, 5,710 nmol/liter) within 20 min of injection and then declined with a median (range) half-life (t 1/2) of 30 (3 to 67) min. ARTS was hydrolyzed rapidly and completely to the biologically active metabolite dihydroartemisinin (DHA). Peak DHA concentrations in plasma ranged between 1,718 and 7,080 nmol/liter (median, 3,060 nmol/liter) and declined with a t 1/2 of 52 (26 to 69) min. In contrast, ARM was slowly and erratically absorbed. The absorption profile appeared biphasic. Maximum ARM concentrations in plasma ranged between 67 nmol/liter (a value close to the 50% inhibitory concentration for some Plasmodium falciparum isolates) and 1,631 nmol/liter (median, 574 nmol/liter) and occurred at a median (range) of 10 (1.5 to 24) h. There was relatively little conversion to DHA. After i.m. injection in cases of severe malaria, absorption of the water-soluble ARTS is rapid and extensive, whereas the oil-based ARM is slowly and erratically absorbed, with relatively little conversion to the more active DHA. On the basis of this pharmacological study, parenteral ARTS is preferable to ARM as an initial antimalarial therapy, particularly in the most seriously ill patients. These findings should be formally assessed by a randomized clinical trial.

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An open randomized comparison of intravenous and intramuscular artesunate in severe falciparum malaria

Transactions of the Royal Society of Tropical Medicine and Hygiene ◽

10.1016/0035-9203(92)90138-3 ◽

1992 ◽

Vol 86 (6) ◽

pp. 584-585 ◽

Cited By ~ 36

Author(s):

Tran Tinh Hien ◽

Nguyen Hoan Phu ◽

Nguyen Thi Hoang Mai ◽

Tran Thi Hong Chau ◽

Tran Thi My Trang ◽

...

Keyword(s):

Falciparum Malaria ◽

Severe Falciparum Malaria ◽

Intramuscular Artesunate

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Faculty Opinions recommendation of Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14736.472252 ◽

2006 ◽

Author(s):

Tomas Jelinek

Keyword(s):

Falciparum Malaria ◽

Randomised Trial ◽

Severe Falciparum Malaria

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Faculty Opinions recommendation of Fluid resuscitation of adults with severe falciparum malaria: effects on Acid-base status, renal function, and extravascular lung water.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717995212.793473859 ◽

2013 ◽

Author(s):

Andrew Davenport

Keyword(s):

Renal Function ◽

Falciparum Malaria ◽

Fluid Resuscitation ◽

Extravascular Lung Water ◽

Acid Base ◽

Lung Water ◽

Acid Base Status ◽

Severe Falciparum Malaria

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Identifying prognostic factors of severe metabolic acidosis and uraemia in African children with severe falciparum malaria: a secondary analysis of a randomized trial

Malaria Journal ◽

10.1186/s12936-021-03785-0 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Grace Mzumara ◽

Stije Leopold ◽

Kevin Marsh ◽

Arjen Dondorp ◽

Eric O. Ohuma ◽

...

Keyword(s):

Prognostic Factors ◽

Metabolic Acidosis ◽

Falciparum Malaria ◽

Model Building ◽

Statistical Significance ◽

Severe Metabolic Acidosis ◽

African Countries ◽

Prognostic Features ◽

African Children ◽

Severe Falciparum Malaria

Abstract Background Severe metabolic acidosis and acute kidney injury are major causes of mortality in children with severe malaria but are often underdiagnosed in low resource settings. Methods A retrospective analysis of the ‘Artesunate versus quinine in the treatment of severe falciparum malaria in African children’ (AQUAMAT) trial was conducted to identify clinical features of severe metabolic acidosis and uraemia in 5425 children from nine African countries. Separate models were fitted for uraemia and severe metabolic acidosis. Separate univariable and multivariable logistic regression were performed to identify prognostic factors for severe metabolic acidosis and uraemia. Both analyses adjusted for the trial arm. A forward selection approach was used for model building of the logistic models and a threshold of 5% statistical significance was used for inclusion of variables into the final logistic model. Model performance was assessed through calibration, discrimination, and internal validation with bootstrapping. Results There were 2296 children identified with severe metabolic acidosis and 1110 with uraemia. Prognostic features of severe metabolic acidosis among them were deep breathing (OR: 3.94, CI 2.51–6.2), hypoglycaemia (OR: 5.16, CI 2.74–9.75), coma (OR: 1.72 CI 1.17–2.51), respiratory distress (OR: 1.46, CI 1.02–2.1) and prostration (OR: 1.88 CI 1.35–2.59). Features associated with uraemia were coma (3.18, CI 2.36–4.27), Prostration (OR: 1.78 CI 1.37–2.30), decompensated shock (OR: 1.89, CI 1.31–2.74), black water fever (CI 1.58. CI 1.09–2.27), jaundice (OR: 3.46 CI 2.21–5.43), severe anaemia (OR: 1.77, CI 1.36–2.29) and hypoglycaemia (OR: 2.77, CI 2.22–3.46) Conclusion Clinical and laboratory parameters representing contributors and consequences of severe metabolic acidosis and uraemia were independently associated with these outcomes. The model can be useful for identifying patients at high risk of these complications where laboratory assessments are not routinely available.

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