Background/Purpose: Tocilizumab (TCZ), an anti–interleukin-6 receptor (IL-6R) monoclonal antibody, was recently approved for the treatment of patients with giant cell arteritis (GCA) based on results of a double-blind randomized controlled trial (RCT) in GCA patients given 162 mg TCZ every week (QW) or every other week (Q2W) by subcutaneous (SC) route (GiACTA trial¹). Another RCT of 8 mg/kg TCZ given intravenously (IV) every 4 weeks (Q4W) also showed positive outcomes in GCA patients.² The double-blind part of each study lasted approximately 1 year. All 3 regimens (SC 162 mg QW, SC 162 mg Q2W, IV 8 mg/kg Q4W) yielded positive outcomes for sustained remission of GCA. However, a higher benefit was noted in some key secondary efficacy outcomes with the QW versus the Q2W SC regimen.¹ The present analysis investigated the pharmacokinetics (PK) of TCZ in GCA patients and assessed the impact of the exposure differential from the 3 regimens on pharmacodynamic (PD) markers.

Methods: TCZ levels and PD biomarkers (soluble IL-6R [sIL-6R], IL-6, erythrocyte sedimentation rate [ESR], and C-reactive protein [CRP]) were measured using validated assays at regular intervals throughout the dosing period from all patients in each trial. PK and PD outcomes were compared to facilitate understanding of the dose exposure–response relationships.

Results: At week 52, mean trough steady state exposure (C_trough), a key PK driver of TCZ efficacy, was highest for SC 162 mg QW, then IV 8 mg/kg Q4W, and finally SC Q2W (Figure). At week 52, sIL-6R levels were similar for the SC QW and IV regimens but lower for the SC Q2W regimen (Figure), possibly demonstrating a higher level of target engagement from the SC QW and IV regimens compared with the Q2W regimen. IL-6 levels increased versus baseline after TCZ administration for all 3 regimens, reflecting displacement of bound, endogenous IL-6 from its receptor, consistent with the mechanism of action of TCZ. ESR levels decreased to a similar extent in response to TCZ administration with all 3 regimens. Change from baseline in CRP was comparable between both SC regimens (~79-93% reduction from baseline from the QW and Q2W regimens, respectively). Quantitative changes in CRP values are not available for the IV study.

Conclusion: Comparison of C_trough after 52 weeks of dosing with TCZ from the 8 mg/kg IV regimen with that obtained from 2 SC regimens showed that exposures from the IV regimen were within the range of exposures of the SC QW and Q2W regimens. Comparison of PD outcomes showed that all 3 regimens had comparable results, except for lower levels of sIL-6R (a mechanistic marker reflecting serum concentration and target engagement) from the SC Q2W regimen. Comparability of PD results is consistent with similar efficacy outcomes in the SC and IV trials. References: 1. Stone JH et al. N Engl J Med 2017;377:317-328. 2. Villiger PM et al. Lancet 2016;387:1921-1927.