Interleukin-6 Inhibitors and Drug-drug Interactions in Patients With Rheumatoid Arthritis

With this study the investigators aim to assess if drug metabolism changes in patients with rheumatoid arthritis when an interleukin (IL)-6 inhibitor is initiated.

Patients with rheumatoid arthritis have an increased level of inflammation in the body which can lead to decreased expression and activity of drug metabolizing enzymes in the liver. This will lead to a decreased metabolism and excretion of drugs. The inflammation is driven by a number of proinflammatory cytokines e.g., IL-6. The investigators hypothesize that patients with rheumatoid arthritis initiating treatment with an IL-6-receptor inhibitor (anti-IL-6R) will obtain a normalization of the activated IL-6-pathway resulting in increased expression and activity of drug metabolizing enzymes and hence increased metabolism. Ultimately, this normalization of drug metabolism could lead to insufficient efficacy of a wide variety of drugs.

The investigators will perform a clinical pharmacokinetic trial. The study will include patients with active rheumatoid arthritis and a need to initiate treatment with an IL-6 receptor antibody. Patients will ingest a 6-drug cocktail consisting of probes for specific CYP enzymes. Plasma and urine will be drawn over 6 hours to determine concentrations of the drugs and their metabolites. Patients will then initiate IL-6 receptor antibody treatment and to assess both short- and long-term impact of altered inflammation, the same 6-drug cocktail will be ingested, and concentrations measured, after three weeks and three months. To help understand the mechanism and the putative involvement of inflammation, markers of inflammation such as cytokines, transcription factors, etc. will also be assesses.

Study Overview

• Status: Terminated
• Conditions: Arthritis, Rheumatoid; Interaction
• Intervention / Treatment: Drug: Tocilizumab; Drug: Sarilumab

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Region Of Southern Denmark
    • Esbjerg, Region Of Southern Denmark, Denmark, 6700
      • Hospital South West Jutland
    • Odense, Region Of Southern Denmark, Denmark, 5000
      • Odense University Hospital
    • Sønderborg, Region Of Southern Denmark, Denmark, 6400
      • Danish Hospital for Rheumatic Diseases

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Active rheumatoid arthritis
• Age 18-75 years
• eGFR > 30 mL/min
• absolute neutrophil count (ANC) ≥ 2 x 109 /L
• Platelet count > 150 x 103 /μL (corresponding to >150 x 109 /L)
• ALAT in the normal range or within 1.5x the upper limit of normal.
• Use of effective contraception (only woman of childbearing potential)
• Negative test for hepatitis and tuberculosis

Exclusion Criteria:

• Known sensitivity to any of the medications used.
• Active severe infections
• Malignancy
• Diverticulitis
• Intake of medications which can influence the safety of the patient or the results of the study. Can include prescription medications, over-the-counter medications, herbal medicines or dietary supplements. Will be assessed by the investigators.
• Participation in other clinical intervention trials.
• Pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Interleukin 6 receptor antibody; Tocilizumab, 162 mg subcutaneous, once every week OR Sarilumab, 200 mg subcutaneous, once every two weeks.

Drug: Tocilizumab; Tocilizumab and Sarilumab are considered equal. Patients are assigned the treatment based on national and local guidelines. Intervention will be administered according to the approved posology.; Other Names: RoActemra; Drug: Sarilumab; Tocilizumab and Sarilumab are considered equal. Patients are assigned the treatment based on national and local guidelines. Intervention will be administered according to the approved posology.; Other Names: Kevzara

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Short-term change in CYP3A4 activity assessed by midazolam metabolic ratio.	A change in metabolic ratio of midazolam after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of midazolam is used to assess the activity of CYP3A4.	3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long-term change in CYP3A4 activity assessed by midazolam metabolic ratio.	A change in metabolic ratio of midazolam after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of midazolam is used to assess the activity of CYP3A4.	12 weeks
Short-term change in CYP1A2 activity assessed by caffeine metabolic ratio.	A change in metabolic ratio of caffeine after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of caffeine is used to assess the activity of CYP1A2.	3 weeks
Long-term change in CYP1A2 activity assessed by caffeine metabolic ratio.	A change in metabolic ratio of caffeine after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of caffeine is used to assess the activity of CYP1A2.	12 weeks
Short-term change in CYP2B6 activity assessed by efavirenz metabolic ratio.	A change in metabolic ratio of efavirenz after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of efavirenz is used to assess the activity of CYP2B6.	3 weeks
Long-term change in CYP2B6 activity assessed by efavirenz metabolic ratio.	A change in metabolic ratio of efavirenz after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of efavirenz is used to assess the activity of CYP2B6.	12 weeks
Short-term change in CYP2C9 activity assessed by losartan metabolic ratio.	A change in metabolic ratio of losartan after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of losartan is used to assess the activity of CYP2C9.	3 weeks
Long-term change in CYP2C9 activity assessed by losartan metabolic ratio.	A change in metabolic ratio of losartan after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of losartan is used to assess the activity of CYP2C9.	12 weeks
Short-term change in CYP2C19 activity assessed by omeprazole metabolic ratio.	A change in metabolic ratio of omeprazole after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of omeprazole is used to assess the activity of CYP2C9.	3 weeks
Long-term change in CYP2C19 activity assessed by omeprazole metabolic ratio.	A change in metabolic ratio of omeprazole after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of omeprazole is used to assess the activity of CYP2C9.	12 weeks
Short-term change in CYP2D6 activity assessed by metoprolol metabolic ratio.	A change in metabolic ratio of metoprolol after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of metoprolol is used to assess the activity of CYP2C9.	3 weeks
Long-term change in CYP2D6 activity assessed by metoprolol metabolic ratio.	A change in metabolic ratio of metoprolol after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of metoprolol is used to assess the activity of CYP2C9.	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in inflammation assessed by measurement of a panel of cytokines.	A change in inflammation after 3 and 12 weeks of treatment with an IL-6Ra as compared to baseline. measured by a panel of inflammatory markers.	3 weeks and 12 weeks

Collaborators and Investigators

• Sponsor: University of Southern Denmark
• Collaborators: Odense University Hospital; Sygehus Lillebaelt; Odense Patient Data Explorative Network; Hospital of South West Jutland; King Christian X´Hospital for Rheumatic Diseases
• Investigators: Principal Investigator: Ann-Cathrine Dunvald, MD, University of Southern Denmark

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2021
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): September 30, 2022

Study Registration Dates

• First Submitted: March 23, 2021
• First Submitted That Met QC Criteria: April 10, 2021
• First Posted (Actual): April 13, 2021

Study Record Updates

• Last Update Posted (Actual): January 25, 2023
• Last Update Submitted That Met QC Criteria: January 20, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: AKF-398

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No