Effect of Coadministered Fat on the Tolerability, Safety, and Pharmacokinetic Properties of Dihydroartemisinin-Piperaquine in Papua New Guinean Children with Uncomplicated Malaria

Abstract

g Coadministration of dihydroartemisinin-piperaquine (DHA-PQ) with fat may improve bioavailability and antimalarial efficacy, but it might also increase toxicity. There have been no studies of these potential effects in the pediatric age group. The tolerability, safety, efficacy, and pharmacokinetics of DHA-PQ administered with or without 8.5 g fat were investigated in 30 Papua New Guinean children aged 5 to 10 years diagnosed with uncomplicated falciparum malaria. Three daily 2.5:11.5-mg-base/kg doses were given with water (n ‫؍‬ 14, group A) or milk (n ‫؍‬ 16, group B), with regular clinical/laboratory assessment and blood sampling over 42 days. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and DHA was assayed using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models for PQ and DHA were developed using a population-based approach. DHA-PQ was generally well tolerated, and initial fever and parasite clearance were prompt. There were no differences in the areas under the concentration-time curve (AUC 0 -ؕ ) for PQ (median, 41,906 versus 36,752 g · h/liter in groups A and B, respectively; P ‫؍‬ 0.24) or DHA (4,047 versus 4,190 g · h/liter; P ‫؍‬ 0.67). There were also no significant between-group differences in prolongation of the corrected electrocardiographic QT interval (QT c ) initially during follow-up, but the QT c tended to be higher in group B children at 24 h (mean ؎ standard deviation [SD], 15 ؎ 10 versus 6 ؎ 15 ms 0.5 in group A, P ‫؍‬ 0.067) and 168 h (10 ؎ 18 versus 1 ؎ 23 ms 0.5 , P ‫؍‬ 0.24) when plasma PQ concentrations were relatively low. A small amount of fat does not change the bioavailability of DHA-PQ in children, but a delayed persistent effect on ventricular repolarization cannot be excluded. Dihydroartemisinin-piperaquine (DHA-PQ) is a widely used artemisinin combination therapy (ACT) that has proved highly effective in a range of studies of children and adults with uncomplicated falciparum or vivax malaria (1). However, in a recent large-scale multiarm randomized trial in Papua New Guinean (PNG) children (2), DHA-PQ proved inferior to artemetherlumefantrine for treatment of Plasmodium falciparum infections and was associated with a treatment failure rate above that required by WHO for the adoption of a new antimalarial therapy (3). Among possible explanations for this unexpected result was the fact that the PNG children allocated to receive DHA-PQ took their tablets with water rather than in the fed state, potentially reducing bioavailability (4). Such an effect could be especially important in young children since conventional mg/kg body weight dosing gives rise to relatively low plasma PQ concentrations in this age group (5, 6).Evidence that PQ absorption is proportional to the amount of coadministered fat comes from a variety of studies in healthy adults and adults with uncomplicated malaria. A high-fat meal (typically containing around 50 g fat) is associated with at least a doubling of area under the PQ plasma concentrati...

Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial

“…Chloroquine increases the QT c by a mean of up to 30 msec 0.5 in healthy volunteers [44] , but no malignant arrhythmias or sudden deaths have been reported with recommended antimalarial doses [43] . Piperaquine also has this effect, with studies in children in PNG and Cambodia showing QT c prolongation similar to that in the present study for children treated with artemisinin-naphthoquine [19] , [20] . Repeated piperaquine dosing with the potential for accumulation is not associated with definite cardiotoxicity [45] , and there is no in vitro evidence of torsadogenic or other pro-arrhythmic effects [46] .…”

“…A 12-lead electrocardiograph was taken for measurement of the QT interval. Each QT interval was corrected for heart rate using Bazett's formula ( ) to allow comparisons with other studies in the PNG pediatric population involving antimalarial drugs with effects on ventricular repolarization in which this correction has been applied [11] , [19] , [20] .…”

Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

“…Food intake was not controlled in the Thai study (14). Although a small amount of fat (Ͻ10 g) does not increase PQ bioavailability (47)(48)(49), greater fat intake, such as that associated with a normal meal, can as much as double relative bioavailability (50)(51)(52). It is possible that the women in the Thai study, whether pregnant or not, consumed increasing amounts of fat as they recovered from malaria, progressively increasing bioavailability as a result of the lipophilicity of PQ.…”

Validation and Application of a Dried Blood Spot Assay for Biofilm-Active Antibiotics Commonly Used for Treatment of Prosthetic Implant Infections

“…One-, two-, and three-compartment models (ADVAN-1, -3, and -11) with zero-, first-, and mixed-order absorption were tested. A transit compartment model for absorption, previously used successfully for anti-infective agents (23)(24)(25), was also tested given the significant variability in the absorption phase. For the RIF/Des-RIF model, additional compartments for Des-RIF were added after the structure of the RIF model was obtained.…”