Population Pharmacokinetics and Exposure-Response Analyses of Sarilumab in Patients with Polymyalgia Rheumatica.

Abstract

Sarilumab (interleukin-6 receptor inhibitor) is approved in the United States and Europe for polymyalgia rheumatica (PMR). This study characterized sarilumab pharmacokinetics (PK) and assessed the influence of intrinsic and extrinsic factors on PK in patients with PMR and giant cell arteritis (GCA). Exposure-responses analyses were conducted to evaluate the PK-pharmacodynamic (PD) relationships of sarilumab with key efficacy and safety endpoints in patients with PMR (NCT03600818). Population (Pop) PK analysis was conducted using pooled PK data from two phase III studies including 58 patients with PMR and 40 with GCA (NCT03600805). This Pop PK model was developed by re-estimating parameters from a previous rheumatoid arthritis (RA) model. The main source of intrinsic PK variability in patients with PMR was body weight, with decreasing weight causing increased sarilumab exposure. The population mean apparent clearance for patients with PMR was lower than for patients with RA due to higher albumin, lower creatinine clearance, and lower C-reactive protein (CRP) in PMR than in RA. Individual exposures at steady state overlapped among patients with PMR, GCA, and RA. PK-PD relationships showed that greater sarilumab C_trough in patients with PMR were associated with increasing total sIL-6Rα and decreasing CRP. There was a slight increase in patients achieving sustained remission at Week 52 and a decrease in absolute neutrophil count with increasing sarilumab C_trough plateauing at 20-25 mg/L. The PD effect of sarilumab plateaued at C_trough of 20-25 mg/L for target saturation, efficacy, and safety endpoints, supporting a dosage of 200 mg every 2 weeks for PMR.