CT.gov identifier NCT01844804.

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Aims Describe population pharmacokinetics of intravenous (IV) and subcutaneous (SC) tanezumab across Phase 2b/3 studies of osteoarthritis and chronic low back pain. Methods Data from 10 studies of IV or SC tanezumab (2.5–20 mg every 8 wk for up to 56 wk) were included in a multistep analysis. In Step 1, a 2‐compartment model with linear and nonlinear elimination (based on prior analysis of pre‐2015 IV osteoarthritis studies) was expanded to include other pre‐2015 studies. In Step 2, post‐2015 SC studies were combined into the model. Steps 3 and 4 evaluated impact of baseline nerve growth factor (NGF) and treatment‐emergent anti‐drug antibodies (TE ADA). Results SC bioavailability was estimated at 62–76%. The key disposition parameters CL, Vc, Vp and KM were estimated to be 0.133 L d−1, 2.6 L, 1.77 L and 31.2 μg L−1, respectively. Plasma tanezumab concentration was predicted to reach Cmax at 8.9–11.2 days following single and multiple SC administration in typical patients within the dose range of SC Phase 3 studies (2.5–10 mg every 8 wk). Exposure of a typical patient was similar between IV and SC for the second part of the dosing interval (wk 4–8). Covariates selected on the absorption parameters were weight, age, sex and injection site. Baseline NGF had minimal effect on maximum elimination capacity and TE ADA status was associated with slightly higher tanezumab clearance (6–7%). Conclusion Our model adequately described plasma tanezumab concentration vs. time following IV or SC administration. Weight was the most influential covariate with respect to absorption of tanezumab in comparison to patient population (osteoarthritis and chronic low back pain) or other demographics. There was no clinically relevant effect of baseline NGF or TE ADA on tanezumab PK.

Abstract. The American Association of Pharmaceutical Scientists (AAPS) biosimilar focus group on nonclinical and clinical assays has developed this manuscript to guide the industry on best practices and testing strategies when developing neutralizing antibody (NAb) assays for biosimilar programs. The immunogenicity assessment to biosimilar and originator drug products is one of the key aspects of clinical programs for biosimilars to demonstrate biosimilarity. Establishing that there are no clinically meaningful differences in immune response between a proposed product and the originator product is a key element in the demonstration of biosimilarity. It is critical to collect, evaluate, and compare the safety and immunogenicity data from the clinical pharmacology, safety, and/or efficacy studies especially when the originator drug product is known to have potential for immune-mediated toxicity. This manuscript aims to provide a comprehensive review and recommendations on assay formats, critical reagents, approaches to method development, and validation of the neutralizing antibody assays in extrapolation within the scope of biosimilar drug development programs. Even if there are multiple options on the development and validation of NAb assays for biosimilar programs, the type of drug and its MoA will help determine the assay format and technical platform for NAb assessment (e.g., cell-based or non-cell-based assay). We recommend to always perform a one-assay approach as it is better to confirm the biosimilarity using one-assay for NAb. If a one-assay approach is not feasible, then a twoassay format may be used. This manuscript will provide all the details necessary to develop NAb assays for biosimilars.

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