Drug InteractionsPhase 1NCT00964106
Validation Study of Multiple Probe Compounds for Drug Interaction Evaluation
A Phase 1 study testing Caffeine, Rosiglitazone and Flurbiprofen in people with Drug Interactions, run by GlaxoSmithKline at 2 sites in South Korea.
Trial summary
The purpose of this study is to identify and validate a probe cocktail for use in future drug-drug interaction studies. Cytochrome P450 enzymes and transport proteins play important roles in the disposition of drugs. Read more about this study
- Who is it for?
- Ages 20 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Drug Interactions
- What is being tested?
- Caffeine, Rosiglitazone and Flurbiprofen
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 87 participants
- Where
- 2 sitesSouth Korea
- Study dates
- 26 Aug 2009to 29 Aug 2011
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy as determined by a responsible physician
- Subjects are not poor metabolizers based on genotyping for the major CYP2C9, 2C19, 2D6 alleles
- Male or female between 20 and 50 years of age at the time of screening, inclusive.
- A female subject is eligible to participate if she is of Non-childbearing potential or postmenopausal
- Body weight greater than or equal to 45 kg and BMI within the range 18.5 to 24.9 kg/m2 (inclusive).
- QTc < 450 msec
- Capable of giving written informed consent
- Able to understand and comply with protocol requirements
Who cannot join
- As a result of the medical interview, physical examination, or screening investigations, the Investigator considers the subject unfit for the study.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days (14 days if the drug is a potential enzyme inducer, such as Panaz ginseng, Gingko biloba or St. John's Wort [Hypericum perforatum]) or 5 half-lives (whichever is longer) prior to the first dose of study medication. Herbal medications include, but are not limited to: traditional Chinese, Korean and Japanese medicines, Panaz ginseng, Gingko biloba or St John's wort (Hypericum perforatum) or any Traditional Chinese herbal medicines (TCM) South Asian Ayurvedic medicine, Traditional Korean Medicines and Japanese Kampo.
- Use of caffeine- or theobromine-containing beverages and foods, or alcohol-containing beverages within 72 hours prior to dosing
- Consumption of the following foods or drinks within 72 hrs prior to dosing : red wine, Seville oranges, grapefruits, pommelos, cruciferous vegetables (e.g., broccoli, Brussels sprouts, cabbage, celery), char-grilled meats, grapefruit juice.
- The subject has a positive pre-study drug/alcohol screen
- Urinary cotinine levels indicative of current smoking or history of regular use of tobacco- or nicotine-containing products within two months prior to screening.
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- A positive Hepatitis B surface antigen or positive Hepatitis C antibody at screening.
- A positive test for HIV antibody
- History of regular alcohol consumption within 6 months of the study
- The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, five half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- Systolic blood pressure outside the range of 80 to 140 mmHg, without antihypertensive therapy and no history of hypertension or diastolic blood pressure outside the range of 60 to 85 mmHg, or heart rate outside the range of 50 to 100 beats per minute (bpm) for female and 45 to 100 beats per minute (bpm) for male subjects
- History of syncope or vaso-vagal attacks.
- Pre-existing condition interfering with normal gastrointestinal anatomy or motility, hepatic or renal function, that could interfere with the absorption, metabolism, or excretion of the study drugs.
- Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
- Has a known intolerance or hypersensitivity to aspirin, NSAIDS, or benzodiazepines, or a known intolerance to the active and/or inactive ingredients in omeprazole, dextromethorphan, caffeine, rosiglitazone, pioglitazone, midazolam, rosuvastatin, flurbiprofen, ketoconazole, fluconazole, rifampin, quinidine, gemfibrozil, and fluvoxamine.
- Has any condition or symptom contraindicated for administration of the probe compounds or inhibitors
- History of sensitivity to heparin or heparin-induced thrombocytopenia (if heparin is used to maintain the patency of an intravenous cannula).
- Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
- EGG abnormalities
- Pregnant females or lactating females.
Trial locations and contacts
2 sites in 1 country.
South Korea2 sites
GSK Investigational Site
Busan, 614-735
GSK Investigational Site
Seoul, 110-744
About this study
Official title: An Open-label Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Cytochrome P450 Probe Drugs in Healthy Adult Subjects
The purpose of this study is to identify and validate a probe cocktail for use in future drug-drug interaction studies. Cytochrome P450 enzymes and transport proteins play important roles in the disposition of drugs. Changes in the activity of these pathways can be assessed using probe drugs selected on the basis of their metabolic or transport pathway. This will be a two part study with the same subjects participating in both parts to decrease variability in data. The purpose of Part 1 is to identify a set of probe drugs ('cocktail') which do not interact with one another; groups of healthy volunteers will receive 7 probe drugs individually and as a combination of the 7 drugs given together as a cocktail. Part 2 will assess the performance of the probe cocktail using three known inhibitors (validation). The inhibitors plus probe cocktail will evaluate the ability of the newly established cocktail to accurately quantify metabolizing enzyme or transporter inhibition, representing a fundamental advance in probe cocktail validation and utility for drug development.
Read the detailed description
The primary purpose of this study is to establish a validated drug cocktail, containing up to 7 probes, for assessing the activity of six drug metabolizing enzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 3A4/5) and the OATP1B1 transporter. In Part 1, the study will determine if there are pharmacokinetic interactions among the probe drugs by comparing the pharmacokinetics of the probe drugs when administered alone and in combination (i.e., as a cocktail). In Part 2, the study will evaluate the quantitative performance of the cocktail by examining the effect of select inhibitors on the pharmacokinetics of respective probe drugs when the probe drugs are administered alone versus when administered in the cocktail.
This study aims to establish a standard probe cocktail that can be used for drug-drug interaction studies, with the intention that any subset of the 7-drug cocktail could be selected for study with a drug in development.
In addition, this study will provide a proof-of-principle evaluation of dried blood spot technology as a method to measure drug concentrations in blood samples collected from clinical studies.
- Conditions
- Drug Interactions
- Being tested
- Caffeine, Rosiglitazone, Flurbiprofen, Omeprazole, Dextromethorphan
- Keywords
- inducer, midazolam, inhibitor, rosiglitazone, dextromethorphan, caffeine, cocktail, pioglitazone, omeprazole, CYP, rosuvastatin, probe drug, drug interaction, flurbiprofen
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CaffeineDrug
Caffeine dosed at 100 mg as probe for CYP1A2 pathway
RosiglitazoneDrug
Dosed at 4 mg as probe for CYP2C8 pathway
FlurbiprofenDrug
Dosed at 40 mg, probe for CYP2C9 pathway
OmeprazoleDrug
Dosed at 20 mg, probe for CYP2C19 pathway
DextromethorphanDrug
Dosed at 30 mg, probe for CYP2D6 pathway
MidazolamDrug
Dosed at 3 mg for Part 1, Part 2 cohorts B and C and 1 mg for Part 2 Cohort A, probe drug for CYP3A4/5 pathway
RosuvastatinDrug
Dosed at 10 mg, probe drug for OATP1B1 pathway
KetoconazoleDrug
Dosed at 400 mg once-daily Day 1 through Day 9, inhibitor of CYP3A4
FluconazoleDrug
Dosed at 400 mg x 1 dose on day 1, 200 mg once daily on days 2 through 9, inhibitor of CYP2C9 pathway
RifampinDrug
Dosed at 600 mg x 1 dose on Day 1 and Day 8, inhibitor of OATP1B1 pathway
RosiglitazoneDrug
Dosed at 15 mg, probe drug for CYP2C8 pathway
| Study group | Role | What they receive |
|---|---|---|
| Probe drugs | Experimental | Caffeine 100 mg CYP1A2 Pioglitazone 15 mg CYP2C8 Flurbiprofen 40 mg CYP2C9 Omeprazole 20 mg CYP2C19 Dextromethorphan 45 mg CYP2D6 Midazolam 3 mg (Part 1, Part 2 Cohorts B and C)
1 mg (Part 2 Cohort A) CYP3A4/5 Rosuvastatin 10 mg OATP1B1 Receives: Drug: Caffeine; Drug: Rosiglitazone; Drug: Flurbiprofen; Drug: Omeprazole; Drug: Dextromethorphan; Drug: Midazolam; Drug: Rosuvastatin |
| Default Inhibitors | Experimental | A Ketoconazole 400 mg once-daily Day 1 through Day 9 CYP3A4 B Fluconazole 400 mg x1 dose on Day 1 200 mg once-daily Day 2 through Day 9 CYP2C9 C Rifampin 600 mg x1 dose on Day 1 and Day 8 OATP1B1 Receives: Drug: Ketoconazole; Drug: Fluconazole; Drug: Rifampin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacokinetic parameters
Plasma AUC (0-inf) of probe and metabolite (where applicable) when administered alone, in combination with other probes/inhibitors
Measured: life of study
Secondary outcomes (1)
To assess the safety and tolerability of co-administration of probe drugs
Safety assessed by AE reporting, concurrent medication evaluation, clinical laboratory assessment, ECG, and vital sign assessment
Measured: life of study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Aug 2009 (estimated)
- Study start26 Aug 2009
- Primary completion29 Aug 2011
- Study completion29 Aug 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Drug InteractionsStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 87 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00964106
- Sponsor's protocol ID
- 112684
- Status last verified
- Jan 2018
- First submitted
- 23 Jul 2009
- Last updated
- 4 Jan 2018
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Yes: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
Study at a glance
From the registry record, last updated by the sponsor on 4 Jan 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-label Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Cytochrome P450 Probe Drugs in Healthy Adult Subjects
- ClinicalTrials.gov ID
- NCT00964106
- Acronym / sponsor ID
- 112684
- Conditions
- Drug Interactions
- Keywords
- inducer, midazolam, inhibitor, rosiglitazone, dextromethorphan, caffeine, cocktail, pioglitazone
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 87 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- 26 Aug 2009 (actual)
- Primary completion
- 29 Aug 2011 (actual)
- Study completion
- 29 Aug 2011 (actual)
- First posted
- 24 Aug 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to identify and validate a probe cocktail for use in future drug-drug interaction studies. Cytochrome P450 enzymes and transport proteins play important roles in the disposition of drugs. Changes in the activity of these pathways can be assessed using probe drugs selected on the basis of their metabolic or transport pathway. This will be a two part study with the same subjects participating in both parts to decrease variability in data. The purpose of Part 1 is to identify a set of probe drugs ('cocktail') which do not interact with one another; groups of healthy volunteers will receive 7 probe drugs individually and as a combination of the 7 drugs given together as a cocktail. Part 2 will assess the performance of the probe cocktail using three known inhibitors (validation). The inhibitors plus probe cocktail will evaluate the ability of the newly established cocktail to accurately quantify metabolizing enzyme or transporter inhibition, representing a fundamental advance in probe cocktail validation and utility for drug development.
Detailed description
The primary purpose of this study is to establish a validated drug cocktail, containing up to 7 probes, for assessing the activity of six drug metabolizing enzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 3A4/5) and the OATP1B1 transporter. In Part 1, the study will determine if there are pharmacokinetic interactions among the probe drugs by comparing the pharmacokinetics of the probe drugs when administered alone and in combination (i.e., as a cocktail). In Part 2, the study will evaluate the quantitative performance of the cocktail by examining the effect of select inhibitors on the pharmacokinetics of respective probe drugs when the probe drugs are administered alone versus when administered in the cocktail.
This study aims to establish a standard probe cocktail that can be used for drug-drug interaction studies, with the intention that any subset of the 7-drug cocktail could be selected for study with a drug in development.
In addition, this study will provide a proof-of-principle evaluation of dried blood spot technology as a method to measure drug concentrations in blood samples collected from clinical studies.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Probe drugs | Experimental | Drug: Caffeine, Drug: Rosiglitazone, Drug: Flurbiprofen, Drug: Omeprazole, Drug: Dextromethorphan, Drug: Midazolam, Drug: RosuvastatinCaffeine 100 mg CYP1A2 Pioglitazone 15 mg CYP2C8 Flurbiprofen 40 mg CYP2C9 Omeprazole 20 mg CYP2C19 Dextromethorphan 45 mg CYP2D6 Midazolam 3 mg (Part 1, Part 2 Cohorts B and C) 1 mg (Part 2 Cohort A) CYP3A4/5 Rosuvastatin 10 mg OATP1B1 |
| Default Inhibitors | Experimental | Drug: Ketoconazole, Drug: Fluconazole, Drug: RifampinA Ketoconazole 400 mg once-daily Day 1 through Day 9 CYP3A4 B Fluconazole 400 mg x1 dose on Day 1 200 mg once-daily Day 2 through Day 9 CYP2C9 C Rifampin 600 mg x1 dose on Day 1 and Day 8 OATP1B1 |
Who may qualify
- Ages
- 20 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- Healthy as determined by a responsible physician
- Subjects are not poor metabolizers based on genotyping for the major CYP2C9, 2C19, 2D6 alleles
- Male or female between 20 and 50 years of age at the time of screening, inclusive.
- A female subject is eligible to participate if she is of Non-childbearing potential or postmenopausal
- Body weight greater than or equal to 45 kg and BMI within the range 18.5 to 24.9 kg/m2 (inclusive).
Key exclusion criteria (20 listed)
- As a result of the medical interview, physical examination, or screening investigations, the Investigator considers the subject unfit for the study.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days (14 days if the drug is a potential enzyme inducer, such as Panaz ginseng, Gingko biloba or St. John's Wort [Hypericum perforatum]) or 5 half-lives (whichever is longer) prior to the first dose of study medication. Herbal medications include, but are not limited to: traditional Chinese, Korean and Japanese medicines, Panaz ginseng, Gingko biloba or St John's wort (Hypericum perforatum) or any Traditional Chinese herbal medicines (TCM) South Asian Ayurvedic medicine, Traditional Korean Medicines and Japanese Kampo.
- Use of caffeine- or theobromine-containing beverages and foods, or alcohol-containing beverages within 72 hours prior to dosing
- Consumption of the following foods or drinks within 72 hrs prior to dosing : red wine, Seville oranges, grapefruits, pommelos, cruciferous vegetables (e.g., broccoli, Brussels sprouts, cabbage, celery), char-grilled meats, grapefruit juice.
- The subject has a positive pre-study drug/alcohol screen
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CaffeineCaffeine dosed at 100 mg as probe for CYP1A2 pathway | Drug | Probe drugs |
| RosiglitazoneDosed at 4 mg as probe for CYP2C8 pathway | Drug | Probe drugs |
| FlurbiprofenDosed at 40 mg, probe for CYP2C9 pathway | Drug | Probe drugs |
| OmeprazoleDosed at 20 mg, probe for CYP2C19 pathway | Drug | Probe drugs |
| DextromethorphanDosed at 30 mg, probe for CYP2D6 pathway | Drug | Probe drugs |
| MidazolamDosed at 3 mg for Part 1, Part 2 cohorts B and C and 1 mg for Part 2 Cohort A, probe drug for CYP3A4/5 pathway | Drug | Probe drugs |
| RosuvastatinDosed at 10 mg, probe drug for OATP1B1 pathway | Drug | Probe drugs |
| KetoconazoleDosed at 400 mg once-daily Day 1 through Day 9, inhibitor of CYP3A4 | Drug | Default Inhibitors |
| FluconazoleDosed at 400 mg x 1 dose on day 1, 200 mg once daily on days 2 through 9, inhibitor of CYP2C9 pathway | Drug | Default Inhibitors |
| RifampinDosed at 600 mg x 1 dose on Day 1 and Day 8, inhibitor of OATP1B1 pathway | Drug | Default Inhibitors |
| RosiglitazoneDosed at 15 mg, probe drug for CYP2C8 pathway | Drug | Probe drugs |
Primary outcome
Pharmacokinetic parameters
Time frame: life of study
Plasma AUC (0-inf) of probe and metabolite (where applicable) when administered alone, in combination with other probes/inhibitors
1 secondary outcome
To assess the safety and tolerability of co-administration of probe drugs
Time frame: life of study
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Jan 2018.
- Results for study 112684 can be found on the GSK Clinical Study Register.Link provided by the sponsor.
- Individual participant dataSharing planned: Yes. Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
GSK Clinical Trials study director
GlaxoSmithKline
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Caffeine, Rosiglitazone and Flurbiprofen in people with Drug Interactions, run by GlaxoSmithKline at 2 sites in South Korea.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pharmacokinetic parameters (time frame: life of study). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Jan 2018.