{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T20:31:48Z","timestamp":1770150708513,"version":"3.49.0"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T00:00:00Z","timestamp":1731542400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JOR Spine"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Bacterial 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\u2009mg\/mL micronized powder, for intradiscal administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Micronization, 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Micronized linezolid, formulated as a powder suspension using a vehicle containing poloxamer 407 and iohexol, provided a temperature\u2010dependent radio\u2010opaque gel that was suitable for image\u2010guided percutaneous intradiscal administration. Efficacy in a sheep model of intradiscal <jats:italic>Staphylococcus aureus<\/jats:italic> infection was demonstrated. The formulation provides a high level of sheep disc tissue exposure, with C<jats:sub>max<\/jats:sub> of 6500\u2009\u03bcg\/g and limited systemic exposure, with a plasma C<jats:sub>max<\/jats:sub> of 0.04\u2009\u03bcg\/mL per 0.1\u2009mL dose (5\u2009mg 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Linezolid can be formulated for image\u2010guided 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jsp2.70010","type":"journal-article","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T11:57:26Z","timestamp":1731585446000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Preclinical development and characterisation of <scp>PP353<\/scp>, a formulation of linezolid for intradiscal administration"],"prefix":"10.1002","volume":"7","author":[{"given":"Graham","family":"Hagger","sequence":"first","affiliation":[{"name":"RVC Business Royal Veterinary College  Hatfield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Guest","sequence":"additional","affiliation":[{"name":"Persica Pharmaceuticals Ltd  Kent UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Birchall","sequence":"additional","affiliation":[{"name":"Evotec (UK) Ltd  Cheshire UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alys","family":"Bradley","sequence":"additional","affiliation":[{"name":"Charles River Laboratories Ltd  Currie UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlie","family":"Brindley","sequence":"additional","affiliation":[{"name":"Kinetassist Ltd.  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