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

• Grant number: 22/10335-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2022
• End date: May 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Vera Lúcia Lanchote
• Grantee: Lucas Alves Pereira
• 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

Abstract

The study aims to develop pharmacokinetic-pharmacodynamic (PK-PD) models of the antibiotics rifampicin, isoniazid, pyrazinamide and ethambutol in macrophages derived from human monocytes of THP-1 lineage infected and not infected with M. tuberculosis H37Rv strains. Macrophage PK-PD data from antibiotics will be incorporated into population pharmacokinetic models in plasma of tuberculosis patients to generate PK-PD models capable of estimating antibiotic exposure and response at the site of infection and of conceptually customizing the dose to optimize treatment. Mononuclear monocytes of THP-1 lineage will be differentiated to macrophages and then infected with M. tuberculosis H37Rv. Infected or uninfected macrophages will be treated in media containing rifampicin, isoniazid, pyrazinamide and ethambutol at different concentrations. The concentrations of rifampicin, 25-O-desacetyl rifampicin, isoniazid, acetyl isoniazid, pyrazinamide and ethambutol will be evaluated in macrophages, macrophage treatment media and in plasma by high performance liquid chromatography coupled to a mass spectrometer (LC-MS/ MS). Antibiotic concentrations and mycobacterial counts in macrophages will be determined and in vitro PK-PD models of antibiotics will be developed by non-linear mixed-effects modeling. In the clinical study will be investigated 24 patients with tuberculosis treated with daily doses of rifampicin, isoniazid, pyrazinamide and ethambutol, co-infected or not with HIV in treatment with antiretrovirals. Models of antibiotic plasma population pharmacokinetics will be developed based on antibiotic plasma concentrations, demographic, genetic and phenotypic characteristics through nonlinear mixed-effects models implemented in the NONMEM program. Plasma pharmacokinetic models and macrophage PK-PD modeling will be combined to explore dose adjustments of the antibiotics rifampicin, isoniazid, pyrazinamide and ethambutol considering antibiotic exposure and activity at a cellular level based on macrophage biochemistry.