Authors:

Noah Strawhacker

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About Paper:

Current treatment of Mycobacterium tuberculosis (TB) relies on an intensive four-drug oral regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol. Though often effective, this approach can lead to suboptimal outcomes, including the emergence of drug resistance from underexposure in the lungs and significant toxicity from overexposure in the liver and kidneys. Preliminary rodent studies support inhaled delivery of anti-TB drugs as a safer and more effective alternative to the traditional oral dose, leading to increased antibiotic concentration in the lungs, where infection lesions primarily occur. However, the impact of these inhaled antibiotics in humans remains unclear. To address this gap, a whole-body population-level pharmacokinetic model was developed to simulate time-dependent concentrations of an oral versus inhaled dose of rifampin in critical organ systems. Using this model, clinically relevant metrics - including area under the curve (AUC) and peak concentration (Cmax) - were calculated for key organ systems in a simulated patient cohort. Using target values for these metrics from the literature, the cumulative fraction of response (CFR) of TB for each dosing method was then obtained. Model predictions indicate that inhaled rifampin improves CFR in the lungs and plasma while reducing liver exposure, suggesting both greater efficacy and decreased side effects compared to the standard oral approach. These findings support the potential of inhaled rifampin as a safer and more effective therapy for TB. Future work may include the model's adaptation to a large-scale screening of TB drug delivery methods and extending its application to the treatment of other pulmonary infections. † Presenting Undergrad Author; ‡ Contributing Undergrad Author; * Undergrad Acknowledgment Keywords: Tuberculosis; Rifampin; Pharmacokinetics; Pharmacodynamics; Computational Modeling

Source:

Purdue University / 2025

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Co-authors:

Noah Strawhacker