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

• Grant number: 21/13605-4
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: February 28, 2022
• End date: February 27, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Vera Lúcia Lanchote
• Grantee: Glauco Henrique Balthazar Nardotto
• Supervisor: Elin Svensson
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Uppsala University (UU), Sweden
• Associated to the scholarship: 16/05624-0 - Pharmacokinetic-pharmacodynamic models (PK-PD) in macrophages and tuberculosis patients with application in personalized dose of rifampicin, isoniazid, pyrazinamide and ethambutol, BP.PD

Abstract

Tuberculosis (TB) is a major cause of ill health and one of the leading causes of death worldwide. Until the coronavirus (COVID-19) pandemic, TB was the leading cause of death from a single infectious agent, ranking above HIV/AIDS. Rifampicin, isoniazid, pyrazinamide, and ethambutol are currently the first-line anti-tuberculosis drugs (FLATDs) that are administered simultaneously according to the patient body weight in fixed-dose combined tablets. This BEPE study aims to assess concentrations and activity of FLATDs in macrophages infected with Mycobacterium tuberculosis H37Rv that will be combined to population pharmacokinetic models in plasma of pulmonary tuberculosis patients to generate quantitative PK-PD models able to relate the dose amount, plasma exposure, distribution, activity at cellular level and influence of individual characteristics. This approach potentially can allow new insights into the rationale for dose adjustment in the target patient population and explore individualized dose accounting the exposure and activity of antibiotics at cellular level based on macrophage and M. tuberculosis biology. Preliminary results show the systemic exposure (AUC0-24) (geometric mean and 95% CI) of FLATDs of TB-HIV+ group was 18.38 (13.3 to 27.82), 238.21 (191.09-296.95) and 18.33 (14.56-23.09) µgh/ml, respectively. Similar drug exposures were found in the TB-HIV group. The geometric mean and 90% CI of the ratios between the groups suggests no significant pharmacokinetic influence of both HIV and the antiretrovirals in FLATDs PK. Besides that, the systemic exposure to pyrazinamide may be below the values considered usual in both groups of patients. The free fat mass (FFM) influenced the clearance of RIF by an allometric relation. Although individuals with low FFM should receive lower doses of RIF, yet, they are higher than the current recommended dose, and these individuals could benefit from a higher RIF dose. (AU)