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

University Hospitals (UH)

Status

Unknown

Conditions

Inflammation

Treatments

Diagnostic Test: CYP phenotyping

Study type

Observational

Funder types

Other

Identifiers

NCT03262051

2016-02232

Details and patient eligibility

About

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

Enrollment

106 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

--> 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