Non-tuberculous mycobacterial lung disease (NTM-LD) caused by Mycobacterium avium complex is a serious chronic infection causing permanent lung damage, and is difficult to treat, typically requiring 12-24 months of treatment with rifampin, macrolide and ethambutol. We hypothesize that combined deuterated ambroxol and [acyl-13C]INH will allow both pharmacokinetic and pharmacodynamic enhancement of Rif activity against MAC to dramatically improve therapy. To test this hypothesis we propose these aims. Specific Aim 1. Determine the resistance of deuterated ambroxol and controls to Cyp3A4 metabolism using Supersomes. We will use industry standard Corning® Cyp3A4 Supersomes™ to determine resistance of ambroxol-d2 to in vitro metabolism using HPLC, MS and 13C-NMR assays. Specific Aim 2. Quantify rifampin, [acyl-13C]INH and ambroxol-d2 efficacy by combination treatment activity against a clinical isolate of Mycobacterium avium in a chronic mouse aerosol infection model. The model will also evaluate the ability of a combination treatment to penetrate the established granuloma and access the internalized bacilli. At the end of this Phase 1 STTR project we will have determined whether deuteration can solve the Cyp3A4 metabolic liability of Amb, and whether ambroxol-d2 and [acyl-13C]INH, separately and combined can potentiate MAC treatment in in a highly predictive mouse model, setting the stage for Phase 2 proposal.
Public Health Relevance Statement: Rifampin is a mainstay of tuberculosis treatment, but relatively little further development of this class of compounds has occurred for 40 years. We have found that ambroxol, a widely approved over the counter medicine, potently amplifies rifampin activity. However, in humans, a drug-drug interaction will lower ambroxol levels when given with rifampin. We will make and test a deuterated version of ambroxol, designed to be resistant to this drug-drug interaction.
Project Terms: Aerosols; Affect; Age-Years; Amikacin; amikacin liposome; Antibiotics; Autophagocytosis; Bacillus; Biological Assay; Cell Wall; Chemicals; Chemosensitization; Chronic; chronic infection; Clinical; course development; CYP3A4 gene; design; Development; Disease; dosage; Dose; drug development; Drug Interactions; Drug Kinetics; Drug resistance; Ethambutol; Granuloma; Guidelines; High Pressure Liquid Chromatography; Human; Hydrophobicity; improved; In Vitro; in vivo; Industry Standard; Infection; Inhalation; isoniazid; Lung diseases; lung injury; Macrolides; Medicine; Metabolic; Metabolism; Modeling; mortality; mouse model; Mus; Mycobacterium avium; Mycobacterium avium Complex; mycolate; non-tuberculosis mycobacteria; Organism; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; pharmacokinetics and pharmacodynamics; Phase; Production; programs; Protocols documentation; Publishing; Rattus; Refractory Disease; Regimen; Reporting; Resistance; Rifampin; Rodent; Small Business Technology Transfer Research; Sputum; stable isotope; Structure of parenchyma of lung; Testing; Toxic effect; Tuberculosis; tuberculosis treatment; Work
