Ontogeny of hepatic efflux transporters and their implication in optimizing pediatric dose of cefoperazone

• Grant number: 14/06526-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2014
• End date: January 31, 2018
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Vera Lúcia Lanchote
• Grantee: Daniel Valente Neves
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 15/15087-0 - Ontogeny of hepatic efflux transporters and its implication in optimizing pediatric dose of ceftriaxone, BE.EP.PD

Abstract

The study evaluates the ontogeny of hepatic transporter BCRP employing modeling PK-PD (pharmacokinetic-pharmacodynamic) of ceftriaxone in pediatric patients with respiratory tract infection. Twelve healthy adults volunteers will be investigated in order to evaluate the population pharmacokinetics of ceftriaxone and set the strategy for sparse sampling (3 samples) for use in the pediatric population. In the first stage of the study, healthy adult volunteers will be divided into 3 groups according to the use or not of eltrombopag as BCRP transporter inhibitor. A group of four healthy volunteers will be treated with one dose of 1g of ceftriaxone (infusion over 2-4 min), another group of four healthy volunteers is treated with two doses of 25 mg eltrombopag orally , the first dose will be in the day before ceftriaxone administration and the second dose will be 4h before the administration of 1g of ceftriaxone ( infusion over 2-4 min ), while the last group of four healthy volunteers will be treated with two doses of 50 mg eltrombopag orally, the first dose will be in the day before ceftriaxone administration and the second dose will be 4h before the administration of 1g of ceftriaxone (infusion over 2-4 min). Pediatric patients requiring iv ceftriaxone will be treated with doses of 50 mg/kg. Three samples of blood will be collected until 48 hours after the first dose of ceftriaxone. The analysis of allelic variants of BCRP efflux transport protein gene will be performed by extracting DNA from whole blood of patients. Ceftriaxone will be analyzed in plasma as total concentration and free concentration using LC-MS/MS. The minimum inhibitory concentration (MIC) of ceftriaxone will be evaluated as pharmacodynamic parameter. The pharmacokinetics of ceftriaxone will be evaluated through non-compartmental model and first-order kinetics. Statistical tests will be performed with the GraphPad InstatÒ software to obtain the mean, median, standard of the mean (SEM) error and a confidence interval of 95 % (95 % CI). The Population Experiment Design (PoPED) software will be used to implement the collection of sparse samples for pharmacokinetic analysis in pediatric patients. The PK/PD analysis will be performed using the NONMEN software (non-linear mixed effect modeling) based on pharmacokinetic parameter plasma concentrations of ceftriaxone not bound to plasma proteins and pharmacodynamic parameter measurements as the minimum inhibitory concentration (MIC) of this cephalosporin. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

NEVES, DANIEL VALENTE; VIEIRA, CAROLINA PINTO; ROCHA, ADRIANA; LANCHOTE, VERA LUCIA. Therapeutic Doses of Eltrombopag do not Inhibit Hepatic BCRP in Healthy Volunteers: Intravenous Ceftriaxone as a Model. JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, v. 21, p. 236-246, 2018. (14/06526-7)