Abstract:

Objective: To investigate the in vivo drug distribution and drug interaction effects of sudapyridine and bedaquiline as monotherapy and in combination with clarithromycin and clofazimine in a rat model infected with Mycobacterium abscesses. Methods: Liquid chromatography-tandem mass spectrometry was employed to determine the concentrations of sudapyridine in plasma, brain, vertebrae, and lung tissues of S-D rats infected with Mycobacterium abscessus at 20 min, 1 hour, and 16 hours after administration of 45 mg/kg sudapyridine (group A), 45 mg/kg sudapyridine+10 mg/kg clarithromycin (group B), and 45 mg/kg sudapyridine+25 mg/kg clofazimine (group C). Similarly, the concentrations of bedaquiline were measured in plasma, brain, vertebrae, and lung tissues at 1, 4, and 16 hours after administration of 40 mg/kg bedaquiline (group D), 40 mg/kg bedaquiline+10 mg/kg clarithromycin (group E), and 40 mg/kg bedaquiline+25 mg/kg clofazimine (group F). The differences in drug concentrations at the same detection time points and in the same tissue among different groups were analyzed. Results: For sudapyridine, at 20 minutes post-administration, the plasma drug concentration in group B (390.6 (319.6, 621.9) ng/ml) was higher than that in group A (140.2 (79.4, 204.0) ng/ml); at 1 hour post-administration, the lung tissue drug concentration in group C (3478.1 (2570.9, 5322.7) ng/ml) was lower than that in group A (6632.0 (5617.6, 8014.1) ng/ml), with both differences being statistically significant (U=0.000, P=0.004; U=4.000, P=0.025). For bedaquiline, at 4 hours post-administration, the plasma drug concentration in group F (2264.6 (1724.4, 3826.0) ng/ml) and at 16 hours post-administration, the plasma and lung tissue drug concentrations (2045.0 (1922.8, 3757.1) ng/ml and 25095.3 (13083.2, 30438.4) ng/ml) were all higher than those in group D (1415.3 (671.9, 1779.0) ng/ml, 879.4 (640.9, 954.5) ng/ml, 8671.0 (4086.1, 13530.3) ng/ml), with all differences being statistically significant (U=3.000, P=0.016; U=0.000, P=0.004; U=2.000, P=0.010). At 16 hours after administration, the drug concentrations in plasma and lung tissue in group A (2505.9 (1844.7, 2986.8) ng/ml and 23481.4 (16988.0, 35219.7) ng/ml) were significantly higher than those in group D (879.4 (640.9, 954.5) ng/ml and 8671.0 (4086.1, 13530.3) ng/ml), with both differences being statistically significant (U=5.000, P=0.037; U=2.000, P=0.010). Conclusion: Compared to monotherapy, the combination of sudapyridine with clarithromycin may increase its exposure level in vivo, and the exposure levels in plasma and lung tissue 16 hours after administration were higher than those of bedaquiline. It can provide a theoretical basis for constituting the anti-MAB therapy regimen.

Key words: Preclinical drug evaluation, Drug synergism, Drug monitoring, Tissue distribution, Clarithromycin, Sudapyridine