Studying intrapulmonary pharmacokinetics for tuberculosis treatment: a systematic review of methodology.

Objectives: Drug concentrations at the site of disease in pulmonary tuberculosis (TB) remain limitedly available, while adequate exposures of anti-TB drugs in the lungs are required for sterilization of lesions. Intrapulmonary concentration data could benefit TB treatment optimization. We conducted a systematic review to identify methods that can be used for sampling, quantifying, describing and predicting intrapulmonary pharmacokinetics of anti-TB drugs in humans.

Methods: Two systematic search strategies were conducted in databases Embase and PubMed, last searched on 18 July 2024. In total, 253 studies were identified, and their applied methods were classified into three different categories: (i) sampling techniques, (ii) quantitative analysis and (iii) modelling methods. All types of pulmonary diseases were included in the search.

Results: Sputum sampling was reported as sampling method in nine studies, tissue biopsy in 51, bronchoalveolar lavage in 115, bronchoscopic microsampling in eight, bronchoabsorption in one and microdialysis in 12 studies. LC-MS/MS, the gold standard for drug quantification in biological samples, was used in 67 studies. Other quantification methods included positron emission tomography, reported in 12 studies and matrix-assisted laser desorption ionization mass spectrometry on lung tissue in three studies. For prediction and description of (pre)clinical intrapulmonary concentration data, population pharmacokinetic modelling was reported in 32 studies and physiologically based pharmacokinetic modelling in 35 studies.

Conclusions: Many of the identified methods are associated with considerable limitations including invasiveness, complexity, cost and lack of standardization. Most importantly, the method of choice must provide adequate representation of site of disease pharmacokinetics. Determining the best approach for studying intrapulmonary pharmacokinetics involves careful consideration of all these factors.