Project Summary/Abstract The global burden of mycobacterial infections remains staggering, with over 10 million new tuberculosis (TB) cases and 1.2 million deaths in 2019, and a recent rising incidence of nontuberculous mycobacteria (NTM). Treatment of both TB and NTM is hindered by the need for prolonged combination antibiotics, drug resistance, toxicity, drug-drug interactions and sub-optimal efficacy. After decades without many new agents, there are now concerted efforts to identify and integrate novel drugs, optimize existing drugs, and augment host immune response. Clinical pharmacology, when integrated throughout drug development, defines critical relationships between drug exposure and effect (or toxicity), identifies key interactions, and enhances treatment success. However, to date, there is a dearth of physician scientists with dual training in infectious diseases and clinical pharmacology who can champion these drug development efforts, especially for NTM. In this proposal, the candidate will apply clinical pharmacology tools to the problem of mycobacterial therapeutics and utilize the resources and framework of three funded clinical trials that are being led by mentors and advisory committee members. Backed by a strong multidisciplinary advisory team with expertise in clinical pharmacology, mycobacterial drug development, pharmacometrics, and mycobacteriology, the candidate will 1) define the pharmacokinetics-pharmacodynamics (PK-PD) of azithromycin for Mycobacterium avium complex (MAC) lung disease by applying the early bactericidal activity (EBA) trial design (Aim 1); 2) identify predictors of toxicity for a novel nitroimidazole antibiotic using PK-toxicodynamic (PK-TD) modeling (Aim 2); and 3) determine the magnitude of drug-drug interaction (DDI) between first-line TB treatment and pravastatin as host-directed therapy (Aim 3). Each one of these aims will provide an opportunity to not only learn but also implement pharmacologic analytical methods for the investigation of both TB and NTM. The candidate will gain skills including population PK modeling, execution of early bactericidal activity trial design, PK-toxicodynamic modeling, and development of a clinical toxicity prediction tool. This K23 Mentored Patient-Oriented Research Career Development Award will serve not only to advance research in mycobacterial therapeutics, but also support the candidate to gain the skills necessary to perform fundamental and advanced clinical pharmacology analyses, lead clinical trials, and form strong multi- institutional collaborations. Upon completion of this K23, the candidate will be well positioned as an independent clinical investigator with expertise in infectious diseases, applied antimycobacterial pharmacology, and NTM therapeutics.

Project narrative The proposed research will apply principles of clinical pharmacology in order to better define the therapeutic window and optimal use of three drugs used in the treatment of mycobacterial infections. This project aims to establish the bactericidal kinetics of standard of care for Mycobacterium avium complex lung disease, define the pharmacokinetics (PK)-toxicodynamic (TD) relationships for a novel nitroimidazole antibiotic, and describe the magnitude of drug-drug interaction between first-line tuberculosis treatment and a promising agent for adjunctive host-directed therapy. The knowledge gained by this proposal through these diverse yet complementary aims will strengthen the science of tuberculosis and nontuberculous mycobacteria therapeutics.