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Population pharmacokinetics of artemether and dihydroartemisinin following single intramuscular dosing of artemether in African children with severe falciparum malaria

Mithwani, S., Aarons, L., Kokwaro, G. O., Majid, O., Muchohi, S., Edwards, Geoffrey, Mohamed, S., Marsh, Kevin and Watkins, W. (2004) 'Population pharmacokinetics of artemether and dihydroartemisinin following single intramuscular dosing of artemether in African children with severe falciparum malaria'. British Journal of Clinical Pharmacology, Vol 57, Issue 2, pp. 146-152.

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Abstract

Aims
To determine the population pharmacokinetics of artemether and dihydroartemisinin in African children with severe malaria and acidosis associated with respiratory distress following an intramuscular injection of artemether.
Methods
Following a single intramuscular (i.m.) injection of 3.2 mg kg(-1) artemether, blood samples were withdrawn at various times over 24 h after the dose. Plasma was assayed for artemether and dihydroartemisinin by gas chromatography-mass spectrometry. The software program NONMEM was used to fit the concentration-time data and investigate the influence of a range of clinical characteristics (respiratory distress and metabolic acidosis, demographic features and disease) on the pharmacokinetics of artemether and dihydroartemisinin.
Results
A total of 100 children with a median age of 36.4 (range 5-108) months were recruited into the study and data from 90 of these children (30 with respiratory distress and 60 with no respiratory distress) were used in the population pharmacokinetic analysis. The best model to describe the disposition of artemether was a one-compartment model with first-order absorption and elimination. The population estimate of clearance (clearance/bioavailability, CL/F) was 14.3 l h(-1) with 53% intersubject variability and that of the terminal half-life was 18.5 h. If it was assumed that artemisin displays 'flip-flop' kinetics, the elimination half-life was estimated to be 21 min and the corresponding volume of distribution was 8.44 l, with an intersubject variability of 104%. None of the covariates could be identified as having any influence on the disposition of artemether. The disposition of dihydroartemisinin was fitted separately using a one-compartment linear model in which the volume of distribution was fixed to the same value as that of artemether. Assuming that artemether is completely converted to dihydroartemisinin, the estimated value of CL/F for dihydroartemisinin was 93.5 l h(-1), with an intersubject variability of 90.2%. The clearance of dihydroartemisinin was formation rate limited.
Conclusions
Administration of a single 3.2 mg kg(-1) i.m. dose of artemether to African children with severe malaria and acidosis is characterized by variable absorption kinetics, probably related to drug formulation characteristics rather than to pathophysiological factors. Use of i.m. artemether in such children needs to be reconsidered.

Item Type: Article
Uncontrolled Keywords: artemether children intramuscular injection malaria population pharmacokinetics cerebral malaria plasmodium-falciparum metabolic-acidosis clinical-features healthy-subjects quinine bioavailability chromatography lumefantrine indicators
Subjects: QV Pharmacology > QV 38 Drug action.
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
WS Pediatrics > WS 20 Research (General)
WS Pediatrics > Diseases of Children and Adolescents > By System > WS 300 Hemic and lymphatic system
WS Pediatrics > By Age Groups > WS 430 Infancy
WS Pediatrics > By Age Groups > WS 440 Preschool child
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1046/j.1365-2125.2003.01986.x
Depositing User: Martin Chapman
Date Deposited: 27 Feb 2013 12:23
Last Modified: 06 Feb 2018 13:03
URI: https://archive.lstmed.ac.uk/id/eprint/2130

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