QUININE PHARMACOKINETICS IN YOUNG-CHILDREN WITH SEVERE MALARIA

Children less than two years of age represent a substantial proportion of severe malaria cases in Africa. The standard treatment is parenter al quinine, but little is known about the pharmacokinetics and toxicit y of quinine in this age group. We have studied the pharmacokinetics o f quinine after intravenous (iv) and intramuscular (im) administration in a group of 20 children less than two years of age with severe mala ria. A loading dose of 20 mg/kg of quinine dihydrochloride was followe d by 10 mg/kg at 12-hr intervals. The im quinine was very rapidly abso rbed, reaching high peak concentrations of 16.4 +/- 3.7 mg/L (mean +/- SD) in 1.1 +/- 0.4 hr. Mean peak levels after iv administration were also high (17.5 +/- 2.4 mg/L). Free quinine levels at 4 hr postadminis tration ranged from 0.27 to 1.89 mg/L (0.87 +/- 0.53 mg/L). At 2 hr an d 4 hr after commencing treatment, an electrocardiogram showed a signi ficant lengthening of the QRS interval compared with baseline (15.6 +/ - 21.4%; P = 0.007 and 17.3 +/- 21.9%; P = 0.006 at 2 hr and 4 hr, res pectively), whereas this was not observed in a control group of nine o lder children (age range = 24 months to 10 years) receiving the same i m dosage regimen. Free and total quinine levels were not significantly correlated with changes in the QRS interval. Levels of alpha(1)-acid glycoprotein, which binds quinine within the circulation, did not diff er between the younger and the older children. These findings raise th e possibility that young children are more susceptible to quinine toxi city than older children, and indicate the need for further evaluation of quinine dosage regimens in this age group.