Pulmonary pharmacokinetics and lesion penetration of antimicrobials in patients with nontuberculous mycobacterial disease

Abstract

ABSTRACT The intrapulmonary pharmacokinetics of antimicrobial agents used to treat nontuberculous mycobacterial (NTM) pulmonary disease remains poorly characterized, limiting the optimization of dosing regimens. This study characterized the plasma and intrapulmonary pharmacokinetics of azithromycin, ethambutol, rifampicin, clofazimine, and amikacin, as well as their penetration into pulmonary lesion sites. We prospectively enrolled patients undergoing guideline-based treatment for NTM pulmonary disease who were indicated for surgical resection at a single center in Japan. Drug concentrations were measured in the plasma and lung samples and analyzed using a population pharmacokinetic model. The lung lesion site, cavity, or nodule/bronchiectatic lesion was evaluated as covariates of the lung-to-plasma partition ratios. Twenty-four patients were enrolled in the study. The estimated lung-to-plasma partition coefficients and intrapulmonary half-lives were 535-fold and 6.3 months for azithromycin, 40-fold and 2.0 months for ethambutol, 5.2-fold and 6.3 min for rifampicin, 18,800-fold and 22 years for clofazimine, 1.3-fold and 2.3 h for intravenous amikacin, and 1.3-fold and 5.0 h for inhaled amikacin, respectively. Evaluation of drug penetration into cavities and nodular/bronchiectatic lesions showed no clearly reduced concentration compared to a normal lung tissue. The intrapulmonary pharmacokinetic characteristics identified in this study provide valuable information for optimizing antimicrobial dosing regimens in the treatment of NTM pulmonary disease. Furthermore, the absence of clearly reduced drug penetration into lesion sites suggests that lesion phenotype alone may have limited value in guiding antimicrobial selection.