Pulmonary Disposition of Tedizolid

Study Overview

• Assessed the pulmonary disposition of tedizolid in adult volunteers
• Participants received 200 mg of tedizolid phosphate orally every 24 hours for 3 days to reach a steady state
• Bronchoalveolar lavage (BAL) was performed on participants at 2, 6, 12, or 24 hours after the last dose
• Drug concentrations were measured in plasma, BAL fluid, and alveolar macrophages (AM) using liquid chromatography-tandem mass spectrometry (LC-MS/MS)
• Urea correction calculated epithelial lining fluid (ELF) concentrations
• Noncompartmental methods and population pharmacokinetics were used to estimate pharmacokinetic parameters
• Penetration was determined through area under the concentration-time curve (AUC0-24) during the dosing interval for ELF and AM relative to free AUC0-24 (fAUC0-24) in plasma

Key Findings

• Tedizolid penetrates into ELF and AM at levels approximately 40-fold and 20-fold higher than free-drug exposures in plasma

Plasma Characteristics

• Half-life in plasma: 9.23 ± 2.04 hours
• Volume of distribution in plasma: 108.25 ± 20.53 liters
• Total AUC0-24 in plasma: 25.13 ± 5.78 µg·h/ml
• Protein binding: 89.44% ± 1.58%
• Mean fAUC0-24 in plasma: 2.65 ± 0.72 µg·h/ml
• Mean concentrations at 2, 6, 12, and 24 hours in ELF: 9.05 ± 3.83, 4.45 ± 2.18, 5.62 ± 1.99, and 1.33 ± 0.59 µg/ml
• Mean concentrations at 2, 6, 12, and 24 hours in AM: 3.67 ± 1.02, 4.38 ± 2.18, 1.42 ± 0.63, and 1.04 ± 0.52 µg/ml
• ELF and AM penetration ratios: 41.2 and 20.0, respectively
• Mean ELF penetration ratio after population analysis: 39.7

Background on Common Bacterial Pneumonia

• Staphylococcus aureus and Streptococcus pneumoniae are the most common causes of hospital-acquired and community-acquired bacterial pneumonia
• Resistance to antibiotics can be substantial, especially for S. aureus
  • Methicillin resistance reported in upwards of 60% of S. aureus isolates

Current Treatment Limitations

• Few antibiotics are available to treat pneumonia caused by methicillin-resistant S. aureus (MRSA)
• Vancomycin and linezolid are recommended as first-line therapy
  • Agents have limitations, including nephrotoxicity for vancomycin and myelosuppression for linezolid

Tedizolid Phosphate Free Acid (TR-701 FA)

• Prodrug of tedizolid (TR-700)
• Is an oxazolidinone active against common respiratory Gram-positive bacteria
  • Includes methicillin-susceptible and -resistant S. aureus and S. pneumoniae
• MICs for MRSA and pneumococcus are approximately 8-fold lower than those of linezolid

Development and Potential

• Tedizolid phosphate is being developed as IV and oral agents for treating pneumonia due to its spectrum of activity, and near-equivalent oral and intravenous bioavailability
• Murine pneumonia experiment results support the development of this drug
• Achieves bacteriostatic and 1-log CFU killing against S. pneumoniae at a dose 4.6- to 5.5-fold lower than linezolid
• Ratios of free area under the curve (fAUC) to MIC of 10 and 25 in plasma were required for bacteriostasis and a 1-log CFU killing against S. aureus isolates
• Similar pharmacodynamic exposure targets for linezolid
• No current data describes the extent of penetration into the site of infection, there is insight into the possibility of tedizolid phosphate as a potential agent for the treatment of pulmonary infections

Site of Infection and Penetration Estimation

• Epithelial lining fluid (ELF) and alveolar cellular space of the lungs
• Is the presumed site of infection for extracellular organisms such as S. aureus and S. pneumoniae
  • Measurement can be estimated by penetration into the alveolar macrophages

Materials and Methods

• Prospective, open-label, multiple-dose pharmacokinetic study setting
  • Clinical Research Center and Same Day Surgi-Center at Hartford Hospital, Hartford, CT
• Study protocol approval
  • Hartford Hospital Institutional Review Board approval
  • Participants provided written informed consent

Participants

• Consisted of twenty healthy adult volunteers
• Inclusion criteria
  • Males or non-pregnant, nonlactating females
  • 18 to 55 years of age
  • Body mass index (BMI) between 20 to 34.9 kg/m²
  • Considered healthy with no significant underlying medical or surgical history

Exclusion Criteria

• Clinically significant disease or illness
• Allergy to tedizolid phosphate, linezolid, lidocaine, midazolam, or similar anesthetics
• Significant medical abnormalities or abnormal lab values
• Excessive alcohol consumption or use of tobacco/nicotine products
• Use of prescription/nonprescription drugs, vitamins, or dietary supplements
• Use of any investigational drug or previous enrollment in a tedizolid phosphate trial

Procedures

• Plasma samples were collected over a dosing interval and participants were randomized for brochoalveolar lavage (BAL)
• Drug concentrations from samples were determined by the validated liquid chromatography with tandem mass spectrometric detection (LC-MS/MS) and concentrations of tedizolid phosphate were not determined in this study, 200-mg tablets were given
• Blood work samples and testing performed
  • Monoject tube sample for K3 EDTA blood and spun for analysis
  • Protein binding was assessed in triplicates, protein binding calculations performed
  • Fiber optic bronchoscope was used and samples immediately aspirated
  • BAL fluid and supernatant put through machine analysis
    • samples were extracted and prepared against a chromatographic machine to be analysed via mass spectrometry
    • Urea concentrations and colorimetric enzymatic determination also assessed
• Pharmacokinetic Analyses Calculations
  • Linear-log trapezoidal rule
  • weighted error as estimate of bias, bias-adjusted mean weighted squared error used for precision
  • model a three-compartment construct with a lag time
  • Monte Carlo simulations to check point estimates of mean and variances

Overall Study Observations

• Plasma concentrations were at steady state, protein binding ranged from 86.1% to 91.9%, resulting in a steady state fAUC0-24 of 2.65 ± 0.72 µg · h/ml

Safety and Tolerability

• Tedizolid phosphate was well-tolerated by all participants
• Commonly reported adverse events include mild symptoms; bradycardia, headache, and nausea
• Resting heart rate returned to baseline
• Adverse events unrelated to drug administration included inflammation at the blood collection site and sore throat
• Few participants experienced elevations in white blood cell count and resolved after returning for lab tests

Study Conclusions

• Steady-state plasma pharmacokinetics were similar to previously reported data
• Significant drug penetration into both extracellular (ELF) and intracellular (AM) pulmonary compartments
• Population pharmacokinetic estimations correlated
• Demonstrated comparable clearance assessments and robust model consistency
• Indicated greater use of a specific weight of tedizolid phosphate in the setting of pneumonia