Ontogeny of hepatic efflux transporters and its implication in optimizing pediatric dose of ceftriaxone

• Grant number: 15/15087-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: October 01, 2015
• End date: March 31, 2016
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Vera Lúcia Lanchote
• Grantee: Daniel Valente Neves
• Supervisor: Oscar Della Pasqua
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: University College London (UCL), England
• Associated to the scholarship: 14/06526-7 - Ontogeny of hepatic efflux transporters and their implication in optimizing pediatric dose of cefoperazone, BP.PD

Abstract

Ceftriaxone is a third generation cephalosporin available in clinic as broad-spectrum antimicrobial. It is used in paediatric and adult patients for the treatment of various infections, such as urinary tract, respiratory, septicaemia, meningitis and treatment of nosocomial infections caused by pathogens resistant to multiple drugs. However, there is little evidence in the literature regarding the use of this cephalosporin in neonates. The aim of this study is to develop a dosing algorithm based on the population pharmacokinetics of ceftriaxone in healthy subjects and determine the optimal schedule for sparse blood sampling to be used in a prospective clinical study in paediatric patients. The clinical data (n=12) used for the purposes of this analysis were obtained from an ongoing study for in which each subject received a single oral dose of 1 g of ceftriaxone.Pharmacokinetic modelling and study protocol optimisation will be based on nonlinear mixed effects modelling principles and ED-optimality concepts as implemented respectively in the software programmes NONMEM and PopED. These activities will be developed at the University College London (UCL) in London, UK. Allometric scaling will be used to extrapolate drug disposition parameters from adults to children. Predicted parameter estimates will be then used as input for the optimisation procedures, which are aimed at assessing the sampling conditions which maximise parameter precisionIt is anticipated that the possibility of characterising the pharmacokinetic profile of ceftriaxone using a maximum of three blood samples in paediatric patients will provide a major improvement in routine therapeutic drug monitoring. In addition, these data will allow further evaluation of age-related changes in drug disposition and consequently the identification of a suitable dosing regimen for this subgroup of patients.