Population pharmacokinetics of tanezumab following intravenous or subcutaneous administration to patients with osteoarthritis or chronic low back pain

Abstract

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.

Prediction of relative change in free nerve growth factor following subcutaneous administration of tanezumab, a novel monoclonal antibody to nerve growth factor

“…Although the model slightly overestimated the total NGF concentration from around 24 to 32 weeks after each dose, the model generally well-predicted observed concentrations up to around 24 weeks after each dose. As was shown in the previous population PK analysis, 13 predicted tanezumab concentrationtime profiles were generally consistent with the observed profiles across the strata in the VPC assessment, although small differences between predicted and observed concentrations were observed around the LLOQ (Figure S4).…”

“…The ELISA assay used anti‐idiotypic mAb as the capturing protein and a mouse anti‐human IgG (Fc)‐horseradish peroxidase conjugate as detection reagent. Precision of the ELISA assay method, as assessed by the coefficient of variation (%CV), was less than or equal to 6.76 13 . An immunoaffinity liquid chromatography tandem mass spectrometry assay method with LLOQ of 10 pg/mL was validated to determine total NGF in human serum.…”

“…The final population PK model was developed using data from 10 studies of i.v. or s.c. tanezumab, including studies A4091056 and A4091057 13 . Data from Study A4091058 were not included in the model development, but were used for subanalyses.…”

“…studies. 13 Another investigation was conducted to characterize overestimation of TMDD approximation models and…”

“…Additionally, the population PK model used for this analysis was based on more comprehensive population PK analysis using data from 10 i.v./s.c. studies 13 …”