Population pharmacokinetics and pharmacodynamics of lumefantrine in young Ugandan children treated with artemether-lumefantrine for uncomplicated malaria

Background. The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children. Methods. Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine. Results. Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3-fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P =. 0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations. Conclusions. We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted. © 2016 The Author

Dynamics and Stability of the Metal Binding Domains of the Menkes ATPase and Their Interaction with Metallochaperone HAH1

International audience: Human copper-ATPases ATP7A and ATP7Bare essential for intracellular copper homeostasis. The mainroles of the Menkes protein, ATP7A, are the delivery of copperto the secretory pathway and the export of excess copper fromthe enterocytes. The N-terminal domain of membrane proteinATP7A consists of six repetitive sequences of 60−70 aminoacids (Mnk1−Mnk6) that fold into individual metal bindingdomains (MBDs) and bind a single copper ion in the reducedCuI form via two cysteine residues. The structure of each individual MBD is known from nuclear magnetic resonanceexperiments. Here, we were interested in the stability and dynamics of each isolated MBD in their apo and holo forms and theirinteractions with the soluble metallochaperone HAH1 that delivers copper to ATP7A. Using molecular dynamics simulations ofthe MBDs under different conditions, we show that some MBDs (Mnk1 and Mnk5) present large root-mean-square deviationsfrom initial structures or large root-mean-square fluctuations, and great care has to be taken in setting up the simulations. Wepropose that the first MBD, Mnk1, probably important in the transfer of copper between the metallochaperone and ATPase,could be stabilized by interactions with other MBDs, including a domain located in the loop between Mnk1 and Mnk2. Animportant result of this work is the apparent direct correlation between the difference in the fluctuations of the metal binding siteloop in its apo and holo forms and the measured affinity of the MBD for copper. This difference decreases from Mnk1 to Mnk6,Mnk4, and Mnk2 in this order. The study of the exposure to the solvent of the metal and the residues of the metal binding loopof the MBDs also shows different behavior for each MBD. In particular, copper in serine-rich domain Mnk3 and largelyfluctuating domain Mnk5 appears to be more solvent-exposed than in the other MBDs. In the second part of this work, weinvestigated the importance of electrostatics in the MBD−chaperone interactions using different docking programs. Mnk1 andMnk4 present a large electrostatic dipole moment and large stabilizing interaction energies with HAH1. Finally, we propose amodel structure of ATP7A from Mnk6 (E561) to P1413 based on the crystal structure of LpCopA and docking simulations