Abstract Background Central nervous system tuberculosis (CNS TB), including tuberculous meningitis, is a life-threatening condition with high mortality rates 1. Contezolid, a next-generation oxazolidinone antibiotic, has shown comparable efficacy to linezolid but with a significantly improved safety profile 2. This exploratory study evaluated the pharmacokinetics (PK), and blood-brain barrier penetration of contezolid tablets in seven adult patients with CNS TB. Figure 1Concentration-time curves of contezolid in plasma and CSF at steady-stateFigure 2Contezolid CSF plasma concentration ratio Methods Participants received a standardized anti-TB regimen, which includes rifampin: 10 mg/kg/day (maximum 600 mg), isoniazid: 5 mg/kg/day (maximum 600 mg), pyrazinamide: 30 mg/kg/day (maximum 2 g), levofloxacin: 500 mg/day, and dexamethasone and mannitol for adjunctive therapy. In addition to this regimen, contezolid tablets were administered at a dose of 800mg every 12 hours. Blood and cerebrospinal fluid (CSF) samples were collected prior to the first dose and at day 8 for PK assessments. . Drug concentrations were measured by a validated liquid chromatography tandem mass spectrometry method. The steady-state PK parameters of contezolid in plasma and CSF were calculated using a noncompartmental model method. The blood-brain barrier penetration of contezolid was evaluated by the ratio of CSF to plasma drug concentration and exposure. Results At steady-state, the plasma AUC0-12, ss and AUC0-∞, ss were 107. 77±55. 64 mg·h/L and 118. 00±60. 21 mg·h/L, whereas the CSF values were 11. 40±3. 14 mg·h/L and 16. 62±12. 24 mg·h/L, with penetration rates of 10. 58% and 14. 08%, respectively. The Tmax, ss in plasma and CSF were 3 h (1. 5–6 h) and 6 h (3–9 h), and the CSF to plasma drug concentration ratio increased with time, indicating delayed drug entry into the CSF. The T1/2, ss in plasma and CSF were 2. 49 h (1. 17–4. 54 h) and 3. 18 h (1. 39–10. 42 h), suggesting slower elimination in CSF. The plasma clearance (CLssF) and volume of distribution (VssF) were 9. 00±3. 86 L/h and 32. 61±13. 85 L, respectively. Conclusion Contezolid demonstrated moderate CSF penetration, but its CSF concentrations were markedly lower than plasma levels, indicating restricted distribution across the blood-brain barrier. Disclosures All Authors: No reported disclosures
Li et al. (Thu,) studied this question.