Effect of Kidney Function on Drug Kinetics and Dosing in Neonates, Infants, and Children

Neonates, infants, and children differ from adults in many aspects, not just in age, weight, and body composition. Growth, maturation and environmental factors affect drug kinetics, response and dosing in pediatric patients. Almost 80% of drugs have not been studied in children, and dosing of these drugs is derived from adult doses by adjusting for body weight/size. As developmental and maturational changes are complex processes, such simplified methods may result in subtherapeutic effects or adverse events. Kidney function is impaired during the first 2 years of life as a result of normal growth and development. Reduced kidney function during childhood has an impact not only on renal clearance but also on absorption, distribution, metabolism and nonrenal clearance of drugs. 'Omics'-based technologies, such as proteomics and metabolomics, can be leveraged to uncover novel markers for kidney function during normal development, acute kidney injury, and chronic diseases. Pharmacometric modeling and simulation can be applied to simplify the design of pediatric investigations, characterize the effects of kidney function on drug exposure and response, and fine-tune dosing in pediatric patients, especially in those with impaired kidney function. One case study of amikacin dosing in neonates with reduced kidney function is presented. Collaborative efforts between clinicians and scientists in academia, industry, and regulatory agencies are required to evaluate new renal biomarkers, collect and share prospective pharmacokinetic, genetic and clinical data, build integrated pharmacometric models for key drugs, optimize and standardize dosing strategies, develop bedside decision tools, and enhance labels of drugs utilized in neonates, infants, and children

Modification of the Alfven wave spectrum by pellet injection

Alfven eigenmodes driven by energetic particles are routinely observed in tokamak plasmas. These modes consist of poloidal harmonics of shear Alfven waves coupled by inhomogeneity in the magnetic field. Further coupling is introduced by 3D inhomogeneities in the ion density during the assimilation of injected pellets. This additional coupling modifies the Alfven continuum and discrete eigenmode spectrum. The frequencies of Alfven eigenmodes drop dramatically when a pellet is injected in JET. From these observations, information about the changes in the ion density caused by a pellet can be inferred. To use Alfven eigenmodes for MHD spectroscopy of pellet injected plasmas, the 3D MILD codes Stellgap and AE3D were generalised to incorporate 3D density profiles. A model for the expansion of the ionised pellet plasmoid along a magnetic field line was derived from the fluid equations. Thereby, the time evolution of the Alfven eigenfrequency is reproduced. By comparing the numerical frequency drop of a toroidal Alfven eigenmode (TAE) to experimental observations, the initial ion density of a cigar-shaped ablation region of length 4cm is estimated to be n(*) = 6.8 x 10(22) m(-3) at the TAE location (r/a approximate to 0.75). The frequency sweeping of an Alfven eigenmode ends when the ion density homogenises poloidally. Modelling suggests that the time for poloidal homogenisation of the ion density at the TAE position is tau(h) = 18 +/- 4 ms for inboard pellet injection, and tau(h) = 26 +/- 2 ms for outboard pellet injection. By reproducing the frequency evolution of the elliptical Alfven eigemnode (EAE), the initial ion density at the EAE location (r/a approximate to 0.9) can be estimated to be n(*) = 4.8 x 10(22) m(-3). Poloidal homogenisation of the ion density takes 2.7 times longer at the EAE location than at the TAE location for both inboard and outboard pellet injection