Evidence for the Efficacy of a Sustained-Release Inhaled Isoniazid Formulation via Pharmacokinetic/Pharmacodynamic Modeling

Optimization of tuberculosis therapy remains one of the urgent tasks of modern medicine. Pulmonary delivery of antibiotics can improve the effectiveness of tuberculosis treatment, as it ensures high local drug concentrations in the lungs and reduces the risk of systemic side effects. The aim of the study was to substantiate the effectiveness of an inhaled anti-tuberculosis formulation with sustained release of isoniazid using pharmacokinetic and pharmacodynamic modeling. To describe pharmacokinetics, multi-compartment pharmacokinetic models were constructed for oral and pulmonary delivery of isoniazid. Model parameters for oral delivery were determined based on published clinical trial data. The absorption rate for the pulmonary formulation was determined from experimental data on isoniazid permeability through a membrane in an in vitro system. The pharmacodynamic model considered the growth and death of the extracellular population of Mycobacterium tuberculosis depending on drug concentration. Combined pharmacokinetic–pharmacodynamic modeling showed that pulmonary delivery of the drug provides higher local exposure in the epithelial lining fluid at lower plasma concentrations and contributes to more effective suppression of the bacterial population than oral delivery. For a dose of 300 mg over two days, early bactericidal activity (EBA) was: EBA = 0,568 log₁₀ CFU/mL/day (oral delivery); EBA = 0,677 log₁₀ CFU/mL/day (pulmonary delivery, respirable fraction (RF) = 0,6); EBA = 0,688 log₁₀ CFU/mL/day (pulmonary delivery, RF = 1). Total drug exposure in epithelial lining fluid (AUC) over 48 hours was: AUC = 15,31 mg·h/L (oral delivery); AUC = 29,06 mg·h/L (pulmonary delivery, RF = 0,6); AUC = 48,44 mg·h/L (pulmonary delivery, RF = 1). Calculation of extracellular bacterial population dynamics under pulmonary delivery of isoniazid (15 – 450 mg) showed that a daily dose of 50 – 100 mg (RF = 0,6) achieves early bactericidal activity values close to the maximum. Mathematical modeling confirms the advantages of the pulmonary route and serves as an effective tool for dose justification and the development of pulmonary drug formulations.