Pharmacokinetic-pharmacodynamic models (PK-PD) in macrophages and tuberculosis patients with application in personalized dose of rifampicin, isoniazid, pyrazinamide and ethambutol

• Grant number: 16/05624-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2017
• End date: March 31, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Vera Lúcia Lanchote
• Grantee: Glauco Henrique Balthazar Nardotto
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/05616-3 - Clinical pharmacokinetics in infectious diseases, AP.TEM
• Associated scholarship(s): 21/13605-4 - Pharmacokinetic-pharmacodynamic models (PK-PD) in macrophages and tuberculosis patients with application in personalized dose of rifampicin, isoniazid, pyrazinamide and ethambutol, BE.EP.PD

Abstract

This study aims to assess the pharmacokinetics-pharmacodynamics of rifampin, isoniazid, pyrazinamide and ethambutol in macrophages derived from human THP-1 monocyte lineage infected and not infected with strains of Mycobacterium tuberculosis H37Rv. Pharmacokinetic and pharmacodynamic (PK-PD) data of antibiotics in macrophages will be included to population pharmacokinetic model in plasma of patients with TB to generate PK-PD models to assess the exposure and the response of antibiotics at the infection site and conceptually personalize the dose to optimize the treatment. THP-1 mononuclear monocyte lineage will be differentiated to macrophages and then infected with Mycobacterium tuberculosis H37Rv. Infected macrophages or not will be treated in media containing rifampicin, isoniazid, pyrazinamide and ethambutol in different concentrations. Rifampicin, 25-O-deacetyl rifampin, isoniazid, acetyl isoniazid, pyrazinamide and ethambutol concentrations will be assessed in macrophages, macrophages treatment medium and plasma by LC-MS/MS. The concentrations of antibiotics and mycobacteria count in macrophages will be determined and in-vitro PK-PD hierarchical mixed effect models of the antibiotics will be developed. In the clinical study will be enrolled 24 subjects with tuberculosis treated daily with rifampicin, isoniazid, pyrazinamide and ethambutol co-infected or not with HIV treated with anti-retroviruses. The population pharmacokinetics models of the antibiotics will be developed based on their plasma concentrations, demographic, genotypic and phenotypic characteristics through hierarchical mixed effect models implemented in NONMEM. The models of pharmacokinetics in plasma and pharmacokinetics and pharmacodynamics in macrophages will be combined to explore personalized dose considering exposure and activity of antibiotics at cellular level based on macrophage biochemistry. (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)

NARDOTTO, GLAUCO HENRIQUE BALTHAZAR; BOLLELA, VALDES ROBERTO; ROCHA, ADRIANA; DELLA PASQUA, OSCAR; LANCHOTE, VERA LUCIA. No implication of HIV coinfection on the plasma exposure to rifampicin, pyrazinamide, and ethambutol in tuberculosis patients. CTS-CLINICAL AND TRANSLATIONAL SCIENCE, OCT 2021. (18/05616-3, 16/05624-0)