None listed
Conditions
Brief summary
The cytochrome P450 (CYP) superfamily is the main group of enzymes responsible for drug metabolism. There are 5 main enzymes which metabolise the majority of drugs. Their function can be measured in vivo with drug probes. Drug cocktails are several probes simultaneously administered to measure several enzymes simultaneously. The Inje drug cocktail uses a single dose of midazolam, dextromethorphan, omeprazole, losartan and caffeine to measure the five main CYP enzymes. Disease states including hypoxia, cachexia and heart failure are known to affect CYP function but the effect on individual enzymes is unknown. The effect of severe COPD as a clinical phenotype is unknown. We aim to use a modification of the Inje cocktail, including paracetamol, to measure CYP function in patients with severe COPD and compare this to healthy volunteers. The primary outcomes will be oral drug clearance and area-under-the-curve of the concentration-time curve for each study drug. We hypothesise that COPD will inhibit many or all of the studied CYP enzymes and this information can be used to optimise drug dosing in this population.
Interventions
This is a primary pharmacokinetic study. This not a classical intervention study in that the intervention is best considered an investigation.
There are two study arms: arm 1 is 12 healthy volunteers and arm 2 is 12 patients with severe chronic obstructive pulmonary disease (COPD).
The intervention is a single oral dose of 6 drugs taken simultaneously under direct observation:
- midazolam 1mg (taken as 1mg of 1ml/mg liquid, added to 50ml water)
- dextromethorphan 30mg (taken as 30mg of 1mg/
This is a primary pharmacokinetic study. This not a classical intervention study in that the intervention is best considered an investigation. There are two study arms: arm 1 is 12 healthy volunteers and arm 2 is 12 patients with severe chronic obstructive pulmonary disease (COPD). The intervention is a single oral dose of 6 drugs taken simultaneously under direct observation: - midazolam 1mg (taken as 1mg of 1ml/mg liquid, added to 50ml water) - dextromethorphan 30mg (taken as 30mg of 1mg/ml liquid, added to 50ml of water) - losartan 25mg (taken as a single 25mg tablet) - omeprazole 20mg (taken as a single 25mg tablet) - caffeine 130mg and paracetamol 1000mg (taken as two tablets each containing 65mg caffeine and 500mg paracetamol). This is administered to both arms. The dose is following by serial pharmacokinetic sampling of the parent drug and metabolite in plasma and urine for 8 hours. From this, the drug exposure is measured and drug metabolism extrapolated for each drug. The metabolism is compared between the two arms.
Sponsors
Dr Richard McNeill
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Diagnosis
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Healthy volunteers: • Age over 18 years old • Ability to understand and the willingness to sign or verbally consent to a written or verbal informed consent document • Ability to abstain from caffeine for 48 hours prior to the study and for the duration of the pharmacokinetic sampling • Body mass index 18 – 30 Patients with COPD: • COPD with GOLD D severity • Body mass index less than or equal to 25 • Age over 18 years old • Ability to understand and the willingness to sign or verbally consent to a written or verbal informed consent document • Ability to abstain from caffeine for 48 hours prior to the study and for the duration of the pharmacokinetic sampling • Ability to safely swallow tablets
Exclusion criteria
Healthy volunteers: • Known sensitivity or contraindications to any of the cocktail drugs • Concomitant use of any of the study medicines (except caffeine) • Concomitant use of medicines known to be moderate or major inhibitors or inducers of cytochrome P450 • Current smoker • Any medical condition expected to affect study drug metabolism or ability to participate in the study • Pregnancy Patients with COPD: • Known sensitivity or contraindications to any of the cocktail drugs • Concomitant use of any of the study medicines (except caffeine) • Concomitant use of medicines known to be moderate or major inhibitors or inducers of cytochrome P450 • Current smoker • Liver cirrhosis • Active hepatitis • Significant small bowel resection • Oral corticosteroid use in the last 2 weeks • Exacerbation of COPD in the last 2 weeks • Intercurrent illness expected to affect study drug metabolism • Using domiciliary oxygen • Active malignancy • Pregnancy
Outcome results
None listed