Although
artesunate is clearly superior, parenteral
quinine is still used widely for the treatment of severe
malaria. A loading-dose regimen has been recommended for 30 years but is still often not used. A population pharmacokinetic study was conducted with 75 Tanzanian children aged 4 months to 8 years with severe
malaria who received
quinine intramuscularly; 69 patients received a loading dose of 20 mg
quinine dihydrochloride (
salt)/kg of
body weight. Twenty-one patients had plasma
quinine concentrations detectable at baseline. A zero-order absorption model with one-compartment disposition pharmacokinetics described the data adequately.
Body weight was the only significant covariate and was implemented as an allometric function on clearance and volume parameters. Population pharmacokinetic parameter estimates (and percent relative standard errors [%RSE]) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 liters/h (6.50%), 16.7 liters (6.39%), and 1.42 h (21.5%), respectively, for a typical patient weighing 11 kg.
Quinine exposure was reduced at lower
body weights after standard weight-based dosing; there was 18% less exposure over 24 h in patients weighing 5 kg than in those weighing 25 kg. Maximum plasma concentrations after the loading dose were unaffected by
body weight. There was no evidence of dose-related
drug toxicity with the loading dosing regimen. Intramuscular
quinine is rapidly and reliably absorbed in children with severe
falciparum malaria. Based on these pharmacokinetic data, a loading dose of 20 mg
salt/kg is recommended, provided that no loading dose was administered within 24 h and no routine dose was administered within 12 h of admission. (This study has been registered with Current Controlled Trials under registration number ISRCTN 50258054.).