| Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects. | |
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MedLine Citation:
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PMID: 21950338 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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"What this paper adds" statement What is already known about this subject Lowered plasma concentrations of artesunate have been reported in uncomplicated malaria in pregnancy which could risk the life of the mother and fetus. The reason for lowered plasma concentrations in pregnancy is unexplained. Oral artesunate is hydrolysed rapidly in the stomach to the biologically metabolite dihyroartemisinin. What this study adds Following IV artesunate administration for malaria in pregnancy the disposition of artesunate and dihydroartemisinin were similar to controls (the same women studied post-partum without malaria). Whereas higher concentrations of artesunate and dihydroartemisinin were observed after oral administration i.e the disease reduced the pre-systemic metabolism of artesunate. This study did not confirm previous reports and is reassuring regarding current dosing for artesunate in pregnancy. ABSTRACT: Aim: To determine if reported lower plasma concentrations of artemisinin derivatives for malaria in pregnancy result from reduced oral bioavailability, expanded volume of distribution, or increased clearance. Methods: In a randomized cross-over treatment study, pregnant women with uncomplicated falciparum malaria received intravenous artesunate (IV ARS) (4mg/kg) on the first day and oral ARS (4mg/kg) on the second, or, oral on the first and IV on the second, in both groups followed by oral ARS (4mg/kg/day) for 5 days. Plasma concentrations of ARS and dihyroartemisinin (DHA) were measured by liquid-chromatography-mass-spectrometry on days 0, 1, 2 and 6. Controls were the same women restudied when healthy (three months post-partum). Results: IV ARS administration resulted in similar ARS and DHA pharmacokinetics in pregnant women with malaria (n = 20) and in controls (n = 14). Oral administration resulted in higher total drug exposure in pregnancy (AUC (95%CI) in hr×ng/mL/(mg/kg)) of 55.1 (30.1-100.0) versus 26.5 (12.2-54.3) for ARS, P = 0.002 and 673 (386-1130) versus 523 (351-724) for DHA, P = 0.007. The corresponding median absolute oral bioavailability (F%) was 21.7 (12.6-75.1) versus 9.9 (6.0-36.81) for ARS (P = 0.046), and 77.0 (42.2-129) versus 72.7 (42.0-87.7) for DHA, P = 0.033. Total DHA exposure was lower at day 6 in pregnant women with malaria (P < 0.001) compared to day 0 or 1, but not in the controls (P = 0.084). Conclusions: This study demonstrates the effects of malaria on oral ARS drug disposition are greater than those of pregnancy. This probably results from a disease related reduction in first pass metabolism. The data is reassuring regarding current dosing recommendations. |
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Authors:
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Rose McGready; Aung Pyae Phyo; Marcus Rijken; Joel Tarning; Niklas Lindegardh; Warunee Hanpithakpon; Hla Hla Than; Nathar Hlaing; Naw Thida Zin; Pratap Singhasivanon; Nicholas White; François Nosten |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-28 |
Journal Detail:
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Title: British journal of clinical pharmacology Volume: - ISSN: 1365-2125 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7503323 Medline TA: Br J Clin Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society. |
Affiliation:
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Shoklo Malaria Research Unit, PO Box 46 Mae Sot Tak 63110, Thailand Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, OX3 7LJ, United Kingdom. |
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