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ANNEX 3. Pharmacology of antimalarial medicines

3.6 ml/min/kg compared with 2.3 ± 1.4 ml/min/kg), and half-life shorter (6.3 ± 1.8 h
compared with 10.1 ± 3.4 h). Concentration at 12 h was lower in malnourished children
(3.3 ± 1.6 mg/ml compared with 5.3 ± 1.6 mg/l). There was a significant correlation
between elimination half-life and left mid-arm:head circumference. The ratio between
the area under the curve for hydroxyquinine, the main metabolite of quinine, and that for
quinine was significantly higher in the malnourished group and significantly correlated
with left mid-arm:head circumference ratio, indicating increased metabolism of quinine
in malnourished patients. The authors suggest that the administration interval should
be reduced to 8 h in malnourished children in order to obtain plasma concentrations of
quinine similar to those found in children with normal nutrition. A3
In the third study, from Niger, 40 children were divided into four groups: normally
nourished children with or without cerebral malaria, and malnourished children (>2 SD
below the median value for at least two of the following: weight-for-height, weight-for-age
and height-for-age) with or without cerebral malaria (89). The age range studied was 24–72
months. Patients with kwashiorkor were excluded. All patients received 4.7 mg/kg quinine
base (as 8 mg/kg Quinimax) by intravenous infusion over 4 h. Infusions were repeated
every 8 h for children with cerebral malaria. C max was highest in malnourished children,
and was higher in those without malaria than with malaria (8.5 ± 4.7 mg/l compared
with 7.7 ± 2.0 mg/l); it was lowest in the control groups without and with malaria (3.0 ±
2.1 mg/l and 6.6 ± 3.0 mg/l). There were no differences between the area under the curve
for 0–8 h and elimination half-life for the two malnutrition groups and controls with
malaria, but all were higher than for controls without malaria. Conversely plasma
clearance of quinine and volume of distribution were smaller in these three groups than
in controls without malaria. Alpha 1-glycoprotein plasma concentrations and protein-
bound fraction of the drug were increased in the three groups. Malnourished children
had slower parasite clearance but the difference was not significant. The authors concluded
that severe global malnutrition and cerebral malaria have a similar effect on quinine
pharmacokinetics in children and that cerebral malaria-mediated modifications of
quinine disposition are not potentiated. They recommend that current dosing schedules
should not be altered for children with malnutrition.

• Sulfadoxine-pyrimethamine
No studies exist of sulfadoxine-pyrimethamine kinetics in malnourished patients.
However, observational data from Rwandan refugee children showed that malnourished
children (defined as weight-for-height <80% of the reference median with or without
oedema) were more likely to have treatment failure than children without malnutrition
(86% compared with 58%) (83). Higher initial parasite counts and host immunity, as well
as pharmacokinetic differences, may also have contributed to this finding.

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