Pharmacokinetics of PP353, a formulation of linezolid for intervertebral disc administration, in patients with chronic low back pain and Modic change Type 1: A first‐in‐human, Phase 1b, open‐label, single‐dose study

Background Bacterial infection of the intervertebral disc is difficult to treat because the tissue is usually not vascularized and systemic antibiotic therapy may not reach optimal antibacterial exposure. Here we characterize the safety, tolerability, and pharmacokinetics of PP353, a suspension of micronized linezolid, formulated for direct intervertebral disc administration. Methods The safety, tolerability, and pharmacokinetics of an intradiscal administration of PP353, was assessed in Part A of a Phase 1b study and consisted of a single injection of study drug (3 mL of PP353 and 150 mg linezolid). Clinical assessment included initial safety and tolerability of PP353 with continued follow‐up for 12 months. Assessment of linezolid concentration in plasma samples enabled characterization of the pharmacokinetics. Deconvolution of systemic linezolid was used to estimate intervertebral disc linezolid concentration. Results Intradiscal administration of 3 mL of PP353 (linezolid 50 mg/mL) to the nucleus pulposus was well tolerated with no reported study treatment‐related severe or serious adverse events and resulted in an average geometric mean linezolid plasma Cmax of 1300 ng/mL at 7.27 h post‐administration. The linezolid plasma Cmax observed with intradiscal PP353 is approximately 10% that observed with a standard oral or iv administration of 600 mg linezolid. Pharmacokinetic deconvolution estimated that a single dose of PP353 (150 mg linezolid) provided intradiscal bactericidal concentration of linezolid for 96 h and bacteriostatic exposure for up to 120 h after dosing. Conclusion Intradiscal administration of 3 mL of PP353 is well‐tolerated and based on the pharmacokinetics following a single injection, a two‐dose regimen of PP353 (150 mg linezolid) on Day 1 and Day 5 ± 1 was selected to explore safety, tolerability, pharmacokinetics, and efficacy in Part B of the Persica 002 study. A first‐in‐human Phase 1b study of a formulation of linezolid for intradiscal administration to treat chronic low back pain associated with Modic Type 1 changes demonstrates consistent pharmacokinetics enabling selection of a dose regimen to assess efficacy.