P-1243. Contezolid Tablets for Central Nervous System Tuberculosis in Adult Patients: pharmacokinetic and blood-brain barrier penetration

TL;DR

Contezolid, a new antibiotic, was tested for its ability to reach the brain in patients with central nervous system tuberculosis.

Contribution

This study is the first to evaluate the pharmacokinetics and blood-brain barrier penetration of contezolid in patients with CNS TB.

Findings

Contezolid showed moderate penetration into cerebrospinal fluid but with significantly lower concentrations than in plasma.

The drug's elimination was slower in cerebrospinal fluid compared to plasma.

The study provides pharmacokinetic parameters of contezolid in both plasma and cerebrospinal fluid at steady-state.

Abstract

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

Concentration-time curves of contezolid in plasma and CSF at steady-state

Contezolid CSF plasma concentration ratio

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.

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 (CLss_F) and volume of distribution (Vss_F) were 9.00±3.86 L/h and 32.61±13.85 L, respectively.

Contezolid demonstrated moderate CSF penetration, but its CSF concentrations were markedly lower than plasma levels, indicating restricted distribution across the blood-brain barrier.

All Authors: No reported disclosures

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