Population pharmacokinetics of intramuscular quinine in children with severe malaria

Abstract

We present the first population pharmacokinetic analysis of quinine in patients with Plasmodium falciparum malaria. Ghanaian children (n = 120; aged 12 months to 10 years) with severe malaria received an intramuscular loading dose of quinine dihydrochloride (20 mg/kg of body weight). A two-compartment model with first-order absorption and elimination gave post hoc estimates for pharmacokinetic parameters that were consistent with those derived from non-population pharmacokinetic studies (clearance [CL] = 0.05 liter/h/kg of body weight; volume of distribution in the central compartment [V(1)] = 0.65 liter/kg; volume of distribution at steady state = 1.41 liter/kg; half-life at beta phase = 19.9 h). There were no covariates (including age, gender, acidemia, anemia, coma, parasitemia, or anticonvulsant use) that explained interpatient variability in weight-normalized CL and V(1). Intramuscular quinine was associated with minor, local toxicity in some patients (13 of 108; 12%), and 11 patients (10%) experienced one or more episodes of postadmission hypoglycemia. A loading dose of intramuscular quinine results in predictable population pharmacokinetic profiles in children with severe malaria and may be preferred to the intravenous route of administration in some circumstances.

FIG. 1

(a) Population pharmacokinetic profile with 95% confidence intervals for quinine after a single intramuscular dose (20 mg/kg). (b) Correlation between the observed quinine plasma levels and the Bayesian estimates predicted by the model.

FIG. 2

Histograms and cumulative distribution graphs for normalized residuals (A), CL (B), V₁ (C), Q (D), and V_p (E).

FIG. 3

(a) Proportion of cases remaining positive for P. falciparum following admission. (b) Median change in parasitemia after admission. Numbers of patients contributing to each value are also given beside the data points.

FIG. 4

Predicted pharmacokinetic profiles of four different doses of quinine based on population estimates: 20 mg/kg (——), 10 mg/kg (−−−), 15 mg/kg (--), 20 mg/kg + 10 mg/kg at 12 h (−-−).