Maturation of renal clearance processes

• Grant number: 17/12452-4
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: October 01, 2017
• End date: March 31, 2018
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Natália Valadares de Moraes
• Grantee: Jhohann Richard de Lima Benzi
• Supervisor: Elke H.J. Krekels
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Institution abroad: Universiteit Leiden, Netherlands
• Associated to the scholarship: 15/25728-2 - Influence of the organic cation transporter 2 (OCT2) inhibitor cimetidine and experimental diabetes mellitus on kinetic disposition of gabapentin in rats, BP.MS

Abstract

Paediatric doses are often derived from adult dosages based on bodyweight. However, growing up is related not only to an increased bodyweight but changes in intrinsic activity and expression of drug-metabolizing enzymes, receptors and transporters. Linearly extrapolating the adult dose to children based on bodyweight may result in intoxication, therapeutic failure or even fatalities. Therefore, new approaches are needed to develop evidence-based drug dosing guidelines for children. Population pharmacokinetic modelling using non-linear mixed effect allows for the characterization of pharmacokinetic processes and identification and quantification of inter-individual differences. Identification of patient-characteristics that can explain part of the inter-individual variability will allow for the definition of appropriate paediatric drug dosing regimen for individual patients. The objective of this project is the characterization of renal maturation profiles. Renal elimination of drugs involves glomerular filtration, metabolic degradation, and active tubular transport. The research group at the LACDR has previously characterized the maturation of glomerular filtration by quantifying the clearance of aminoglycosides that are mainly eliminated through glomerular filtration. The focus will now be on the maturation of active tubular processes, which will be studied by quantifying the clearance of drugs for which elimination is dependent on both glomerular filtration and active tubular processes, examples of these drugs are lamivudine and cefazoline. As the maturation of glomerular filtration is already known, the maturation of active tubular processes can be derived.