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

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

Study Overview

• Status: Recruiting
• Conditions: Inflammation
• Intervention / Treatment: Diagnostic test: CYP phenotyping

• Study Type: Observational
• Enrollment (Anticipated): 106

Contacts and Locations

• Study Contact: Name: Caroline Samer, MD; Phone Number: +41 22 382 99 47; Email: caroline.samer@hcuge.ch

Study Locations

• Switzerland
  • Genève, Switzerland
    • Recruiting
    • Geneva University Hospitals, HUG
    • Contact: Caroline Samer

Participation Criteria

Eligibility Criteria

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

• 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.

Description

--> Inclusion Criteria: For hip surgery and chronic inflammation groups

• 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

  --> Exclusion Criteria: For hip surgery and chronic inflammation groups

• 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
• Hospitalized in intensive care unit at time of inclusion
• Hospitalized in intermediate care unit at time of inclusion
• Active cancer
• HIV infection
• Renal impairment (glomerular filtration rate < 30 mL/min/1.73m2)
• Hepatic impairment (Child-Pugh score B and C)
• Inability to give blood samples
• Sensitivity to any of the drugs used

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patient with acute inflammation (surgery); patients undergoing hip surgery	Diagnostic test: CYP phenotyping; Phenotyping using a simplified version of the Geneva cocktail
Patient with chronic inflammation; patients with rheumatoid arthritis	Diagnostic test: CYP phenotyping; Phenotyping using a simplified version of the Geneva cocktail
Patient with acute inflammation (SARS-CoV-2 infection); patients with SARS-CoV-2 infection	Diagnostic test: CYP phenotyping; Phenotyping using a simplified version of the Geneva cocktail

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the correlation between the activity of CYPs and CRP levels	The routine concentration of the inflammatory marker C-reactive protein (CRP) will be measured in blood	1 week or 3 months
Evaluate the correlation between the activity of CYPs and TNF-α levels	TNF-α blood concentrations will be measured by using the Fluorokine MAP Cytokine Multiplex Elisa.	1 week or 3 months
Evaluate the correlation between the activity of CYPs and IL-1β levels	IL-1β blood concentrations will be measured by using the Fluorokine MAP Cytokine Multiplex Elisa.	1 week
Evaluate the correlation between the activity of CYPs and IFN-γ levels	IFN-γ blood concentrations will be measured by using the Fluorokine MAP Cytokine Multiplex Elisa.	1 week
Assess if tocilizumab reverse the activity of CYP in patients with RA after 3 months of treatment	Comparison of CYP function before and 3 months after the beginning of the Tocilizumab treatment.	3 months
Assess if SARS-CoV-2 infection modify pharmacokinetic parameters of concomitant medications which are CYPs substrates	Comparison of plasma concentrations of CYPs substrates, when COVID-19 patients received any CYPs substrates	3 months
Evaluate the correlation between inflammatory markers, CYP function and intensity of fatigue (MFI) and pain (NRS)	Function and intensity of fatigue will be measured with the validated French version of the Multidimensional Fatigue Inventory; pain will be measured with the numeric rating scale (NRS) 0 to 10 (0 = no pain and 10 = worst pain imaginable).	1 week

Collaborators and Investigators

• Sponsor: University Hospital, Geneva

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2017
• Primary Completion (Anticipated): September 1, 2021
• Study Completion (Anticipated): September 1, 2021

Study Registration Dates

• First Submitted: August 21, 2017
• First Submitted That Met QC Criteria: August 24, 2017
• First Posted (Actual): August 25, 2017

Study Record Updates

• Last Update Posted (Actual): March 4, 2021
• Last Update Submitted That Met QC Criteria: March 2, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: rheumatoid arthritis; surgery; COVID-19; SARS-CoV-2 infection; chronic inflammation; phenotyping; genotyping; acute inflammation; cytochromes P450
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation
• Other Study ID Numbers: 2016-02232

Drug and device information, study documents

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