Gut microbiome in tuberculosis: a challenge in antibiotic pharmacokinetics.

• Grant number: 24/05744-2
• Support Opportunities: Research Grants - Young Investigators Grants
• Duration: December 01, 2024 - November 30, 2029
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: João Paulo Bianchi Ximenez
• Grantee: João Paulo Bianchi Ximenez
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Deanna L Kroetz ; Oscar Della Pasqua ; Peter Turnbaugh ; Valdes Roberto Bollela ; Vera Lúcia Lanchote ; Wilson Araújo da Silva Junior

Abstract

A total of 1.3 million people died from tuberculosis (TB) in 2022 (including 167,000 people with HIV). Worldwide, TB is the second leading infectious killer after COVID-19 (above HIV and AIDS). Rifampicin (RIF) is an essential component among the four first-line anti-tuberculosis drugs (FLATDs), being the other three: isoniazid (INH), pyrazinamide (PZA), and ethambutol (ETH). For antibiotic sensitive disease, the shortest duration of therapy is 2 months of INH/RIF/PZA/ETH, followed by 4 months of INH/RIF (2HRZE/4HR). A key factor that has been identified as contributing to treatment failure in TB is the high variability in anti-TB drug PK. Several factors are known to cause inter- and intraindividual PK variability, including body weight, sex, pharmacogenomics, and comorbid conditions. Numerous studies have indicated that the gut microbiome is an underexplored contributor to intra- and inter-individual variations in the efficacy and toxicity of different therapies. Gut bacteria can metabolize hundreds of host-targeted drugs, in some cases leading to clinically relevant changes in first-pass metabolism or the clearance of drugs in the gut following biliary excretion. Thus, understanding these relationships between therapies and microbiomes are likely to be fruitful in uncovering additional variability in drug response and thus, delivering precision medicine. So far, this is the first study that will explore the gut microbiome's role in this variability. First, we will conduct a longitudinal cohort study in at least 60 drug-sensitive TB patients in both HIV-positive and HIV-negative with pulmonary cavities on chest radiograph, and high sputum bacillary load. Participants will be enrolled at after two months of anti-TB therapy (2HRZE/4HR). TB patients will be orally administered subtherapeutic doses of the following probe drugs: caffeine (10 mg) as a probe for CYP1A2, omeprazole (2 mg) to determine CYP2C9 activity, losartan (2 mg) as a CYP2C19 marker, midazolam (0.2 mg) to phenotype for CYP3A, metoprolol (10 mg) as a probe for CYP2D6, fexofenadine (10 mg) to evaluate P-gp transporting activity, rosuvastatin (2 mg) as a probe for OATP1B1, BCRP, and UGT, and furosemide (40 mg) to evaluate OAT1 and OAT3 transporting activity. Sequential blood, urine and stool samples will be collected over a 24-hour period after the administration of FLATDs and ART for pharmacokinetics, pharmacogenetics, and microbiome analyses. Pharmacokinetics analysis will be develop applying LC-MS/MS, for pharmacogenetics analysis we will apply qPCR, and we will use Illumina sequencer for microbiome analysis. Second, we will develop a microbiome-based model applying pharmacometrics modeling and simulation to integrative analysis of pharmacokinetics, pharmacogenetics and microbiome will identify bacterial species that could explain the anti-TB and ART drugs plasma exposure variability. Upon successful completion of the proposed JP research, we expect our contribution to 1) Establish the previously undescribed impact of the human gut microbiome as a significant covariate to explain the heterogeneity of the pharmacokinetics of anti-TB drugs in patients with and without HIV, 2) Demonstrate the distinctive relationship between metabolism enzymes and drug transporters activities and gut microbiome among TB patients with and without HIV, and 3) Assess the divergence in gut microbiome between TB patients without and with HIV under ART treatment. These contributions will be significant because they are expected to provide strong scientific justification for a novel mechanism for the previously unexplained variability of anti-TB drug PK. (AU)