Impact of Acute and Chronic Inflammation on Cytochromes P450 Activity Measured With Dried Blood Spot

NCT03262051 | Unknown

• 1 other identifier: 2016-02232
• Study Type: observational
• Target: 106
• Locations: 1 country
• Sites: 1

Brief Summary

Cytochromes P450, main enzymes of drug metabolism, play a prominent role in the first-pass metabolism of oral substances. Inter-individual variability in their activity due to genetic and environmental factors has been observed and may be associated with adverse therapeutic outcomes (ineffectiveness or toxicity). The inflammation, whether acute or chronic, can theoretically modulate the pharmacokinetics of drugs by modulating enzyme activity. Indeed, in vitro data and animal models, as well as more limited data in humans, indicate a down-regulation of CYP in the context of inflammation. The cocktail approach developed and validated in Geneva ("cocktail Geneva") measures the activity of several CYP simultaneously using micro-doses of probe drugs and facilitating sampling (10uL capillary blood) on a dried blood spot. We intend to measure the activity of CYP in an acute inflammation model (hip surgery and SARS-CoV-2 infection) and chronic inflammation (rheumatoid arthritis, RA). The effect of the biological agent tocilizumab (anti IL-6 receptor) in a treated patient subgroup (patients treated regardless of our study) will be measured after 3 months of treatment. The main objective is to determine if interleukin 6 levels are correlated with the activity of CYP450 in patients with acute (orthopedic surgery - hip or SARS-CoV-2 infection) or chronic inflammation (RA). Secondary objectives are:

• To correlate CYPs activities with the levels of other inflammatory markers (CRP, TNF-α, IL-1β, IFN-γ);
• To assess correlation between markers of inflammation, CYP activities and the intensity of fatigue and pain;
• To assess if tocilizumab reverse CYP activity in patients with RA after 3 months treatment;
• To assess if SARS-CoV-2 infection modify pharmacokinetic parameters of concomitant medications which are CYPs substrates

Conditions

Inflammation

Keywords

cytochromes P450; chronic inflammation; genotyping; phenotyping; acute inflammation; rheumatoid arthritis; surgery; COVID-19; SARS-CoV-2 infection

Outcome Measures

Primary Outcomes (1)

• Evaluate the impact of IL6 levels on the activity of CYPs in patients with acute (post orthopaedic surgery -hip or post SARS-CoV-2 infection) and chronic (rheumatoid arthritis) inflammation.

  The phenotyping probe drugs used in this study will be given as 2 capsules: one capsule of Omeprazole 10 mg and one capsule containing the remaining probe 'cocktail' drugs (caffeine 50 mg, flurbiprofen 10 mg, dextromethorphan 10 mg, midazolam 1 mg, bupropion 20 mg). The enzymatic activities of the following CYP will be assessed by specific metabolite/probe single point concentration ratios (metabolic ratios-MR) in capillary blood: * CYP1A2 * CYP2B6 * CYP2C9 * CYP2C19 * CYP2D6 * CYP3A4

  1 week

Secondary Outcomes (7)

• Evaluate the correlation between the activity of CYPs and CRP levels

  1 week or 3 months

• Evaluate the correlation between the activity of CYPs and TNF-α levels

  1 week or 3 months

• Evaluate the correlation between the activity of CYPs and IL-1β levels

  1 week

• Evaluate the correlation between the activity of CYPs and IFN-γ levels

  1 week

• Assess if tocilizumab reverse the activity of CYP in patients with RA after 3 months of treatment

  3 months

Study Arms (3)

Patient with acute inflammation (surgery)

patients undergoing hip surgery

Diagnostic Test: CYP phenotyping

Patient with chronic inflammation

patients with rheumatoid arthritis

Diagnostic Test: CYP phenotyping

Patient with acute inflammation (SARS-CoV-2 infection)

patients with SARS-CoV-2 infection

Diagnostic Test: CYP phenotyping

Interventions

CYP phenotyping DIAGNOSTIC_TEST

Phenotyping using a simplified version of the Geneva cocktail

Patient with acute inflammation (SARS-CoV-2 infection); Patient with acute inflammation (surgery); Patient with chronic inflammation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients included in the study will be patients with either chronic inflammation (patients with rheumatoid arthritis) or with acute inflammation (patients undergoing hip surgery or with COVID-19). All patients will be recruited at the Geneva University Hospitals.

You may qualify if:

• Male and female patients diagnosed with rheumatoid arthritis or undergoing an elective hip surgery
• Age \> 18 years old
• Understanding of French language and ability to give a written inform consent
• For SARS-CoV-2 infection group
• Male and female patients diagnosed with SARS-CoV-2 infection (positive RT-PCR) and CRP \> 30 mg/L
• Age \> 18 years old
• Understanding of French language and ability to give a written inform consent

You may not qualify if:

• Pregnant or lactating females
• Severe cardiac failure, severe edema or ascites
• Severe COPD or pulmonary embolism requiring oxygen
• Uncontrolled infection
• Active cancer
• HIV infection
• Renal impairment (defined as serum creatinine concentrations \> 1.5 x ULN)
• Hepatic impairment (alteration of hepatic tests AST, ALT, bilirubin, GGT \>2 x ULN)
• Inability to give blood samples
• Sensitivity to any of the drugs used
• Intake of drugs altering CYPs activity (based on \[1\]) except for tocilizumab
• For SARS-CoV-2 infection group
• Pregnant or lactating females
• Active cancer
• HIV infection

Sponsors & Collaborators

• University Hospital, Geneva: lead

Study Sites (1)

Geneva University Hospitals, HUG

Geneva, Switzerland

RECRUITING

MeSH Terms

Conditions

Inflammation; Arthritis, Rheumatoid; COVID-19

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Central Study Contacts

Caroline Samer, MD

CONTACT

+41 22 382 99 47; caroline.samer@hcuge.ch

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Doctor, University Hospital, Geneva

Study Record Dates

• First Submitted: August 21, 2017
• First Posted: August 25, 2017
• Study Start: September 1, 2017
• Primary Completion: September 1, 2021
• Study Completion: September 1, 2021
• Last Updated: March 4, 2021

Record last verified: 2021-03

Locations

CH (1)