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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• 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. WHAT THIS STUDY ADDS• 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. AIMSTo 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. METHODSEighty-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 ml) 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. RESULTSA two-compartment model adequately described the data for both CQ and SDx. For CQ, the typical apparent clearance (CL/F) and volume of distribution (VC/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 VC/F to normalized body weight was 1.6 l kg -1. Post hoc parameter estimates for both drugs showed lower maximum concentrations (Cmax) 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. CONCLUSIONSThe study results suggest that full-strength combination to all children would improve the cure rate.

Artemisinin-Naphthoquine Combination Therapy for Uncomplicated Pediatric Malaria: a Pharmacokinetic Study

“…This finding is consistent with similar pharmacokinetic studies involving chloroquine (21, 23, 32, 52) and piperaquine (48). A number of studies of quinoline and related antimalarial drugs have shown biphasic drug concentration-time profiles that can be analyzed using a two-compartment model (10,19,27,30,39,40,46,47,53). Improved pharmacokinetic study design, including more-frequent sampling of longer duration, as well as lower limits of quantification for the analytical techniques, may explain why recent studies such as ours reveal more-complex elimination kinetics.…”

A review of clinical pharmacokinetics of chloroquine and primaquine and their application in malaria treatment in Thai population

“…A two-compartment model was best fit with the concentration-time profiles of both CQ and DECQ, with a one transit compartment model for the absorption of CQ. This multiexponential decline in blood concentrations of both CQ and DECQ were in consistency with previous reports (Gustafsson et al, 1983;Aderounmu et al, 1986;Karunajeewa et al, 2008;Obua et al, 2008). The mean transit time of absorption (MTT: 0.773 h), peripheral volume of distribution (Vp: 1,600 l), and elimination halflife (t 1/2 : 10.7 days) of CQ were similar to the previously reported values in other populations, but systemic clearance (CL: 6.13 l/h) was relatively lower (FriskHolmberg et al, 1984;Aderounmu et al, 1986;Gustafsson et al, 1987;Tett et al, 1987;Edwards et al, 1988;Titus et al, 1989;Vries et al, 1994;Lee et al, 2008;Karunajeewa et al, 2008;Obua et al, 2008;Karunajeewa et al, 2010;Wetsteyn et al, 2012;Zhao et al, 2014).…”

Adherence to artemether/lumefantrine treatment in children under real-life situations in rural Tanzania

“…27,28 Age-based dosage schedules of ALu might also explain the unpredictable blood concentrations of lumefantrine, since the dose per kg may vary widely between patients, as reported for the CQ/SP combination. 29 This underscores the need to monitor the rate of adherence to treatment guidelines by providers as well as treatment schedules among patients in rural areas when implementing ALu treatment on a wide scale in Africa.…”