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Open Access 01-11-2020 | Sarilumab | Original Research Article
Population Pharmacokinetic–Pharmacodynamic Relationships of Sarilumab Using Disease Activity Score 28-Joint C-Reactive Protein and Absolute Neutrophil Counts in Patients with Rheumatoid Arthritis
Published in: Clinical Pharmacokinetics | Issue 11/2020
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Background
Sarilumab is a human monoclonal antibody blocking the interleukin-6 receptor alpha (IL-6Rɑ) approved for the treatment of moderately to severely active rheumatoid arthritis in adults with inadequate response or intolerance to other disease-modifying antirheumatic drugs.
Objective
The aim of the current analysis was to describe sarilumab exposure–response relationships.
Methods
Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed describing the time course of the 28-joint disease activity score by C-reactive protein (DAS28-CRP) and absolute neutrophil count (ANC) using data from phase I–III studies (NCT01011959, NCT01061736, NCT01709578, NCT01768572) after subcutaneous sarilumab 50–150 mg every week or 100–200 mg every 2 weeks.
Results
The time course of DAS28-CRP and ANC after sarilumab administration was described by semi-mechanistic, indirect-response models. Drug effect was predicted to be numerically greater at median exposure for the 200 mg every 2 weeks regimen versus the 150 mg every 2 weeks regimen, for both DAS28-CRP (50% vs. 47%) and ANC reduction from baseline (39% vs. 31%), with the latter showing less fluctuations within a dosing interval. Four covariates were retained in the final models: body weight, baseline rheumatoid factor status, anti-cyclic citrullinated peptide status, and concomitant methotrexate. There was no clinically meaningful influence of investigated covariates for either model.
Conclusion
The PopPK/PD models showed numerically greater reductions in DAS28-CRP and ANC with sarilumab 200 mg every 2 weeks than with 150 mg every 2 weeks. There was no clinically meaningful influence of investigated covariates. These data contribute to the totality of evidence that supports a sarilumab subcutaneous starting dose of 200 mg every 2 weeks, with a subsequent reduction to 150 mg every 2 weeks in the event of laboratory abnormalities such as neutropenia.