The pharmacokinetics (PK) / pharmacodynamics (PD) of pretomanid, delamanid and bedaquiline in the BALB/c mouse model of central nervous system tuberculosis
Abstract
BACKGROUND: Central nervous system tuberculosis (CNS-TB) is one of the most destructive diseases with high morbidity and mortality worldwide. The present study aimed to assess the effect of three anti-tuberculosis drugs, pretomanid (PA-824), delamanid (DLM) and bedaquiline (BDQ), in CNS-TB treatment, as single agents in the treatment of CNS-TB, using a BALB/c mouse model, and analyze their concentration levels in various organs, including the brain, plasma, lung and spleen. METHODS: Tissue distribution of 3 drugs in healthy mice was determined by high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). The in vivo activities of PA-824, DLM, BDQ were assessed in CNS-TB mice model. RESULTS: The high Kp values of DLM and PA-824 in the brain of mice suggest that they may be well distributed in brain tissue. Compared with untreated mice, after 8 weeks the bacterial load of all treatment groups decreased by 1.0 to 4.7 log10 CFU/lung, and 1.1 to 3.2 log10 CFU/brain, respectively. Among them, PA-824 showed superior efficacy in the brain, owing to its favorable distribution in brain. DLM at a dose of 5 mg/kg showed a certain degree of anti-mycobacterial activity in the brain, although its effect in the lung and spleen was less pronounced. Although BDQ concentration in the mouse brain was not as low as that in patients’ cerebrospinal fluid (CSF), its therapeutic activity in CNS-TB warrants further investigation. CONCLUSIONS: Our findings suggest that PA-824 holds…
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