Population pharmacokinetics of chloroquine and sulfadoxine and treatment response in children with malaria: suggestions for an improved dose regimen

Abstract

* Both chloroquine (CQ) and sulfadoxine/ pyrimethamine (SDx/PYR) remain important drugs in the control of malaria. * The available data on CQ, SDx and PYR are summary pharmacokinetic parameters based on classical/traditional methods, mostly in adults. * No study has described the population pharmacokinetics of a fixed-dose CQ + SDx/PYR combination in children with falciparum malaria. * This study presents population pharmacokinetic data on CQ and SDx in children with uncomplicated falciparum malaria. * The study demonstrates that in age-based fixed-dose regimens with CQ and SDx, drug exposures and outcomes may be correctly predicted, although correlation with body weight is poor. * The study proposes dose modification to improve response with the CQ + SDx/PYR combination. To describe the pharmacokinetics of chloroquine (CQ) and sulfadoxine (SDx), and to identify predictors of treatment response in children with malaria given the CQ + SDx and pyrimethamine (PYR) combination. Eighty-six Ugandan children with uncomplicated falciparum malaria, 6 months to 5 years old, were randomly treated with prepacked fixed-dose CQ + SDx/PYR. The youngest children (<24 months) received half strength and the older (>24 months) full strength treatment. The reported day 14 failure rates were 48% and 18%, respectively. Capillary blood (100 microl) applied on to filter paper was collected on eight occasions during 28 days of follow up. Concentrations of CQ and SDx were determined. A population approach was used for the pharmacokinetic analysis. A two-compartment model adequately described the data for both CQ and SDx. For CQ, the typical apparent clearance (CL/F) and volume of distribution (V(C)/F) values were estimated to be 2.84 l h(-1) and 230 l. The typical CL/F for SDx was 0.023 l h(-1), while the factor relating its V(C)/F to normalized body weight was 1.6 l kg(-1). Post hoc parameter estimates for both drugs showed lower maximum concentrations (C(max)) and concentration-time curve areas (AUC(0,336 h)) in younger children. The AUC(0,336 h) for SDx and CQ were independently significant factors for prediction of cure. Simulations suggest that giving the higher dose to the youngest children would result in higher CQ and SDx concentrations and improved outcome. The study results suggest that full-strength combination to all children would improve the cure rate.