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Preclinical development and characterisation of PP353, a formulation of linezolid for intradiscal administration
Graham Hagger1, Sarah Guest2, Stephen Birchall3
1RVC Business Royal Veterinary College Hatfield UK.
Introduction:
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 mg/mL micronized powder, for intradiscal administration.
Methods:
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.
Results:
Micronized 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 μg/g and limited systemic exposure, with a plasma Cmax of 0.04 μg/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.
Conclusions:
Linezolid 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.
Insights
A novel linezolid formulation for direct injection into the spine shows promise for treating bacterial disc infections and chronic low back pain. This new approach offers targeted delivery and reduced systemic exposure, improving patient outcomes and antibiotic stewardship.
Area of Science:
- Pharmacology
- Infectious Diseases
- Orthopedics
Background:
- Bacterial intervertebral disc infections can cause Modic changes and chronic low back pain.
- Current oral antibiotic treatments require prolonged use and have limitations in efficacy, side effects, and antibiotic stewardship.
- No approved antibiotic formulations exist for direct intradiscal administration.
Purpose of the Study:
- To develop and preclinically characterize a novel linezolid formulation for intradiscal administration.
- To assess the safety, efficacy, and pharmacokinetic profile of the intradiscal linezolid formulation.
Main Methods:
- Micronization techniques and particle size analysis were used to optimize the formulation.
- Ex vivo diffusion assays and gelling temperature estimations informed formulation properties.
- Pharmacokinetic and efficacy studies were conducted in a sheep model of disc infection, alongside a GLP local tolerance study.
Main Results:
- A micronized linezolid powder suspension was developed, forming a radio-opaque gel suitable for image-guided administration.
- The formulation demonstrated efficacy in a sheep model of Staphylococcus aureus disc infection.
- High local drug concentrations (Cmax of 6500 μg/g) and limited systemic exposure (plasma Cmax of 0.04 μg/mL) were observed.
Conclusions:
- Linezolid can be effectively formulated for image-guided percutaneous intradiscal administration.
- The preclinical data support the potential of this formulation for treating bacterial disc infections.
- A Phase 1b clinical trial is underway to evaluate the formulation's safety and efficacy in human patients.
