Preclinical development and characterisation of PP353, a formulation of linezolid for intradiscal administration

Hagger, G; Guest, S; Birchall, S; Bradley, A; Brindley, C; Corbett, D; Cummings, PJ; Freire, C; Harris, J; Wise, A; Wood, M; Czaplewski, LG

Abstract

IntroductionBacterial infection of the intervertebral disc can lead to vertebral endplate edema known as Modic changes, with associated chronic low back pain. Oral antimicrobial therapy has shown efficacy but relies on prolonged dosing and may not be optimal in terms of patient outcome, side effects, or antibiotic stewardship. There is no antibiotic formulation approved for intradiscal administration. Here, we describe the development and preclinical characterization of a formulation of linezolid, a suspension of 50 mg/mL micronized powder, for intradiscal administration.MethodsMicronization, particle size analysis, Franz cell diffusion assays, ex vivo bioassay, and estimates of gelling temperature were used to optimize the composition and properties of the formulation. Performance of the formulation was assessed using sheep to characterize the pharmacokinetics and a model of intradiscal infection was developed to demonstrate efficacy. Suitability for human administration was demonstrated in a Good Laboratory Practice (GLP) local tolerance study.ResultsMicronized linezolid, formulated as a powder suspension using a vehicle containing poloxamer 407 and iohexol, provided a temperature-dependent radio-opaque gel that was suitable for image-guided percutaneous intradiscal administration. Efficacy in a sheep model of intradiscal Staphylococcus aureus infection was demonstrated. The formulation provides a high level of sheep disc tissue exposure, with Cmax of 6500 mu g/g and limited systemic exposure, with a plasma Cmax of 0.04 mu g/mL per 0.1 mL dose (5 mg of linezolid). Deconvolution of plasma linezolid pharmacokinetics correlated with linezolid remaining in the disc over time. Observations from a GLP local tolerance study with the linezolid formulation were of a minor nature and related to the intradiscal administration procedure.ConclusionsLinezolid can be formulated for image-guided percutaneous intradiscal administration. The formulation is now in a Phase 1b clinical trial to evaluate safety, pharmacokinetics, and efficacy in patients with CLBP and suspected bacterial infection.

Citation

Hagger, G., Guest, S., Birchall, S., Bradley, A., Brindley, C., Corbett, D., Cummings, P., Freire, C., Harris, J., Wise, A., Wood, M., & Czaplewski, L. (2024). Preclinical development and characterisation of PP353, a formulation of linezolid for intradiscal administration. JOR Spine, 7(4), https://doi.org/10.1002/jsp2.70010

• Journal Article Type: Article
• Acceptance Date: Oct 10, 2024
• Online Publication Date: Nov 14, 2024
• Publication Date: 2024
• Deposit Date: Jan 27, 2025
• Publicly Available Date: Jan 27, 2025
• Print ISSN: 2572-1143
• Electronic ISSN: 2572-1143
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 4
• DOI: https://doi.org/10.1002/jsp2.70010
• Keywords: intradiscal; linezolid; Modic; pharmacokinetics; vertebrogenic back pain; LOW-BACK-PAIN; PROPIONIBACTERIUM-ACNES; INTERVERTEBRAL DISCS; MODIC CHANGES; SUSCEPTIBILITY; ASSOCIATION; INFECTION; TRIAL