Population Pharmacokinetic-Pharmacodynamic Relationships of Sarilumab Using Disease Activity Score 28-Joint C-Reactive Protein and Absolute Neutrophil Counts in Patients with Rheumatoid Arthritis.

Abstract

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.

• Authors: Lei Ma, Christine Xu, Anne Paccaly, Vanaja Kanamaluru
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 59 Issue 11 Pg. 1451-1466 (11 2020) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 32451909 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antirheumatic Agents
• C-Reactive Protein
• sarilumab
• Methotrexate

Topics

• Adult
• Antibodies, Monoclonal, Humanized (pharmacokinetics, therapeutic use)
• Antirheumatic Agents (pharmacokinetics, therapeutic use)
• Arthritis, Rheumatoid (drug therapy)
• C-Reactive Protein (analysis)
• Female
• Humans
• Male
• Methotrexate (therapeutic use)
• Middle Aged
• Neutrophils (cytology)
• Treatment Outcome