Healthy VolunteersGEM-PKNCT00474201
Drug Interaction Study of Lopinavir/Ritonavir and Gemfibrozil
A study testing Lopinavir/Ritonavir and Gemfibrozil in people with Healthy Volunteers, run by National Institutes of Health Clinical Center (CC) at 1 site in United States.
Trial summary
This study will determine whether the protease inhibitor lopinavir/ ritonavir (Kaletra (Trademark)), which is used to treat HIV disease, lowers blood levels of the lipid-regulating drug gemfibrozil (Lopid (Trademark)) in HIV-negative healthy volunteers. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy Volunteers
- What is being tested?
- Lopinavir/Ritonavir and Gemfibrozil
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 15 participants
- Where
- 1 siteUnited States
- Study dates
- May 2007to Jul 2008
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Age of 18 to 65 years.
- Healthy by medical history and physical exam.
- Test HIV negative.
- Screening laboratory values within institutional normal range.
- Negative serum pregnancy test for females of child-bearing potential within 7 days prior to the initiation of LPV/r.
- Willingness and ability of females of child-bearing potential to practice abstinence or use effective non-hormonal methods of birth control (i.e. condom, diaphragm, IUD, spermicide, etc.) during the study.
- Non-smoker for at least 6 weeks prior to study participation. Subjects who are not currently smoking must refrain from smoking during the entire study period.
Who cannot join
- Concomitant routine therapy with any prescription, over-the-counter, herbal, or holistic medications, including oral contraceptives for 30 days prior to study participation.
- Subjects taking oral contraceptives currently, or within 30 days prior to study initiation.
- Intermittent (PRN) use of acetaminophen, non-steroidal antiinflammatory medications (i.e. ibuprofen), and loperamide will be allowed during the study.
- Subjects will be allowed to take a multivitamin with minerals, or equivalent, once daily if they desire to do so.
- Inability to obtain venous access for sample collection.
- Known presence of diabetes mellitus, human immunodeficiency virus (HIV) infection, active tuberculosis, cardiac disease (hypertension; congestive heart failure etc.), renal disease (chronic or acute renal failure or insufficiency), thyroid disease, hepatitis, respiratory disease (uncontrolled asthma or chronic obstructive pulmonary disease), myasthenia gravis, glaucoma, or uncontrolled peptic ulcer disease. Any other condition that may interfere with the interpretation of the study results or that may not be in the best interest of the subject in the opinion of the investigator.
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- Positive pregnancy test or breastfeeding female.
- The presence of persistent diarrhea or malabsorption that would interfere with the subject's ability to absorb drugs.
- Drug or alcohol use that may impair safety or adherence.
- History of intolerance or allergic reaction (rash; hives; swollen lips; difficulty breathing) to fibric acid derivatives (e.g. gemfibrozil, fenofibrate, bezafibrate, etc.) or protease inhibitors (ritonavir, lopinavir; indinavir, nelfinavir, saquinavir, atazanavir, fosamprenavir, darunavir, tipranavir).
- Inability or unwillingness of females of child-bearing potential to use a non-hormonal (barrier) method of contraception throughout the study (e.g. condom; diaphragm, etc.).
- Non-fasting total cholesterol or triglycerides greater than or equal to 270 mg/dL.
- Participation in another study during the entire study period.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: The Influence of Lopinavir/Ritonavir on Gemfibrozil Pharmacokinetics in Healthy Volunteers
This study will determine whether the protease inhibitor lopinavir/ ritonavir (Kaletra (Trademark)), which is used to treat HIV disease, lowers blood levels of the lipid-regulating drug gemfibrozil (Lopid (Trademark)) in HIV-negative healthy volunteers. Many patients with HIV infection who take protease inhibitors have abnormally high lipids (cholesterol and triglycerides). Gemfibrozil, commonly used to treat high triglycerides, often is not effective in HIV-infected patients taking protease inhibitors, possibly because of an interaction between the two medicines that causes a lowering of gemfibrozil's levels in the blood. Results from this study will give researchers information on whether lopinavir/ ritonavir affects the blood levels of gemfibrozil.
Healthy, normal volunteers between 18 and 65 years old who test negative for HIV may be eligible for this study.
Read more
On study day 1, subjects have a blood sample drawn from a catheter inserted into a vein in the arm to determine pre-dosing blood levels of gemfibrozil. They then take a gemfibrozil tablet and are given breakfast 30 minutes after taking the drug. Blood samples are obtained through the catheter at 0, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing to determine gemfibrozil levels at those intervals. At the end of 12 hours, the catheter is removed and the subject is discharged from the clinic. The next morning subjects return to the clinic for another blood sample, collected through a vein in the arm.
Subjects begin taking lopinavir/ ritonavir between 7 and 35 days after their first dose, depending on their schedule and the clinic schedule. On the fourteenth day of dosing subjects come to the clinic and are given a single dose of gemfibrozil, as on study day 1, and have breakfast 30 minutes later. Blood samples are collected to determine gemfibrozil levels just like on study days 1 and 2. An additional sample is collected for routine lab tests.
Read the detailed description
Hyperlipidemia continues to be a common problem in individuals with HIV, particularly those receiving HIV protease inhibitors (PIs) or the nucleoside reverse transcriptase inhibitor, stavudine. PI-treated patients have been noted to have increases in low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol compared to PI-treatment naive individuals. The prevalence of lipid abnormalities in patients receiving PI-containing therapy has been estimated at 27-57 percent; moreover, cardiovascular complications have begun to be revealed. Triglyceride elevations, in particular, are not only an independent risk factor for the development of coronary artery disease, but may also lead to pancreatitis. Despite treatment with fibric acid derivatives, such as gemfibrozil, TGs typically remain elevated above the upper limit of normal in HIV-infected subjects. One possible reason for persistently elevated TGs in these patients is reduced efficacy of their fibric acid therapy, which may result from an unrecognized drug-drug interaction. Fibric acid derivatives are metabolized in the liver via uridine 5'-diphosphate-glucuronosyl transferase enzymes (UGT), which are induced by the HIV PI ritonavir. Indeed, ritonavir significantly lowers plasma concentrations of other drugs metabolized by this enzymatic system by 40-50 percent. As UGT activity is induced, the metabolism of UGT substrates (gemfibrozil) will increase, resulting in a decrease in their plasma concentrations. Preliminary data in non-HIV-infected subjects suggest that reduced plasma concentrations of gemfibrozil are likely to result in reduced efficacy of the drug. Despite the fact that many HIV-infected patients with hypertriglyceridemia are likely to be receiving triglyceride-lowering therapy with a fibric acid derivative while simultaneously receiving antiretroviral therapy that includes ritonavir (i.e. lopinavir + ritonavir [LPV/r]), these two drugs have not been studied in combination to determine whether or not they interact. The objective of this study is to characterize the impact of LPV/r on the pharmacokinetic (PK) profile of gemfibrozil, after a single 600 mg oral dose, administered to healthy volunteers. In a longitudinal study design, fifteen subjects will receive a single, 600 mg dose of gemfibrozil before and after 13 days of LPV/r 400/100 mg twice daily. Gemfibrozil pharmacokinetics will be determined on days one and 14 and compared using the student t-test. Results from this study will provide (or refute) the rationale for further studies designed to assess the possibility of dose-adjusting gemfibrozil when it is given in combination with ritonavir in order to maximize the pharmacologic effects of gemfibrozil.
- Conditions
- Healthy Volunteers
- Being tested
- Lopinavir/Ritonavir, Gemfibrozil
- Keywords
- Pharmacokinetic, HIV, Drug-Drug Interaction, Lopinavir/Ritonavir, Gemfibrozil, Healthy Volunteer, HV
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lopinavir/RitonavirDrug
Also called lopinavir/ritonavir = Kaletra(TM)
lopinavir 400 mg + ritonavir 100 mg twice daily for 2 weeks
GemfibrozilDrug
Also called gemfibrozil (Teva Pharmaceuticals)
Control arm (no intervention used in this arm)
| Study group | Role | What they receive |
|---|---|---|
| Gemfibrozil PK without LPV/r | Sham comparator | Subjects received a single 600 mg dose of gemfibrozil without concurrent lopinavir-ritonavir 400mg/100mg; this is the "control" arm of a crossover study design. Receives: Drug: Gemfibrozil |
| Gemfibrozil PK after 2 weeks of LPV/r | Experimental | Single dose (600 mg) Gemfibrozil pharmacokinetics (i.e. plasma concentrations collected over time to calculate area under the concentration vs. time curve) assessed after 14.5 days of lopinavir/ritonavir (400/100 mg twice daily) administration. Receives: Drug: Lopinavir/Ritonavir |
What is being measured
The primary outcome is the main question the study is designed to answer.
Gemfibrozil Area Under the Concentration vs. Time Curve (AUC)
AUC (ng*hr/mL) of gemfibrozil when given as a 600 mg dose by itself compared to gemfibrozil AUC after 14.5 days of lopinavir-ritonavir (400mg/100mg) twice daily.
Measured: 22 days per subject (approximately 1 year for entire study completion)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 May 2007 (estimated)
- Study startMay 2007
- Primary completionJul 2008
- Study completionJul 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Healthy VolunteersStudies of the same condition, open and under way.
- 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 N/A
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institutes of Health Clinical Center (CC)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Scott Penzak, Pharm.D., National Institutes of Health Clinical Center (CC)
- Investigators
- Scott R Penzak, Pharm.D., Principal investigator, CC Pharmacy Department
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00474201
- Sponsor's protocol ID
- 070149
- Other IDs
- 07-CC-0149 CL006000-01 CC
- Acronym
- GEM-PK
- Status last verified
- Mar 2012
- First submitted
- 15 May 2007
- Last updated
- 26 Sep 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Busse KH, Hadigan C, Chairez C, Alfaro RM, Formentini E, Kovacs JA, Penzak SR. Gemfibrozil concentrations are significantly decreased in the presence of lopinavir-ritonavir. J Acquir Immune Defic Syndr. 2009 Oct 1;52(2):235-9. doi: 10.1097/QAI.0b013e3181b0610e.
PubMed 19648824
Study at a glance
From the registry record, last updated by the sponsor on 26 Sep 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Influence of Lopinavir/Ritonavir on Gemfibrozil Pharmacokinetics in Healthy Volunteers
- ClinicalTrials.gov ID
- NCT00474201
- Acronym / sponsor ID
- GEM-PK / 070149
- Conditions
- Healthy Volunteers
- Keywords
- Pharmacokinetic, HIV, Drug-Drug Interaction, Lopinavir/Ritonavir, Gemfibrozil, Healthy Volunteer, HV
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- National Institutes of Health Clinical Center (CC)US National Institutes of Health
- Study start
- May 2007
- Primary completion
- Jul 2008 (actual)
- Study completion
- Jul 2008 (actual)
- First posted
- 16 May 2007 (estimated)
- Results
- Posted 9 Apr 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will determine whether the protease inhibitor lopinavir/ ritonavir (Kaletra (Trademark)), which is used to treat HIV disease, lowers blood levels of the lipid-regulating drug gemfibrozil (Lopid (Trademark)) in HIV-negative healthy volunteers. Many patients with HIV infection who take protease inhibitors have abnormally high lipids (cholesterol and triglycerides). Gemfibrozil, commonly used to treat high triglycerides, often is not effective in HIV-infected patients taking protease inhibitors, possibly because of an interaction between the two medicines that causes a lowering of gemfibrozil's levels in the blood. Results from this study will give researchers information on whether lopinavir/ ritonavir affects the blood levels of gemfibrozil.
Healthy, normal volunteers between 18 and 65 years old who test negative for HIV may be eligible for this study.
On study day 1, subjects have a blood sample drawn from a catheter inserted into a vein in the arm to determine pre-dosing blood levels of gemfibrozil. They then take a gemfibrozil tablet and are given breakfast 30 minutes after taking the drug. Blood samples are obtained through the catheter at 0, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing to determine gemfibrozil levels at those intervals. At the end of 12 hours, the catheter is removed and the subject is discharged from the clinic. The next morning subjects return to the clinic for another blood sample, collected through a vein in the arm.
Subjects begin taking lopinavir/ ritonavir between 7 and 35 days after their first dose, depending on their schedule and the clinic schedule. On the fourteenth day of dosing subjects come to the clinic and are given a single dose of gemfibrozil, as on study day 1, and have breakfast 30 minutes later. Blood samples are collected to determine gemfibrozil levels just like on study days 1 and 2. An additional sample is collected for routine lab tests.
Detailed description
Hyperlipidemia continues to be a common problem in individuals with HIV, particularly those receiving HIV protease inhibitors (PIs) or the nucleoside reverse transcriptase inhibitor, stavudine. PI-treated patients have been noted to have increases in low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol compared to PI-treatment naive individuals. The prevalence of lipid abnormalities in patients receiving PI-containing therapy has been estimated at 27-57 percent; moreover, cardiovascular complications have begun to be revealed. Triglyceride elevations, in particular, are not only an independent risk factor for the development of coronary artery disease, but may also lead to pancreatitis. Despite treatment with fibric acid derivatives, such as gemfibrozil, TGs typically remain elevated above the upper limit of normal in HIV-infected subjects. One possible reason for persistently elevated TGs in these patients is reduced efficacy of their fibric acid therapy, which may result from an unrecognized drug-drug interaction. Fibric acid derivatives are metabolized in the liver via uridine 5'-diphosphate-glucuronosyl transferase enzymes (UGT), which are induced by the HIV PI ritonavir. Indeed, ritonavir significantly lowers plasma concentrations of other drugs metabolized by this enzymatic system by 40-50 percent. As UGT activity is induced, the metabolism of UGT substrates (gemfibrozil) will increase, resulting in a decrease in their plasma concentrations. Preliminary data in non-HIV-infected subjects suggest that reduced plasma concentrations of gemfibrozil are likely to result in reduced efficacy of the drug. Despite the fact that many HIV-infected patients with hypertriglyceridemia are likely to be receiving triglyceride-lowering therapy with a fibric acid derivative while simultaneously receiving antiretroviral therapy that includes ritonavir (i.e. lopinavir + ritonavir [LPV/r]), these two drugs have not been studied in combination to determine whether or not they interact. The objective of this study is to characterize the impact of LPV/r on the pharmacokinetic (PK) profile of gemfibrozil, after a single 600 mg oral dose, administered to healthy volunteers. In a longitudinal study design, fifteen subjects will receive a single, 600 mg dose of gemfibrozil before and after 13 days of LPV/r 400/100 mg twice daily. Gemfibrozil pharmacokinetics will be determined on days one and 14 and compared using the student t-test. Results from this study will provide (or refute) the rationale for further studies designed to assess the possibility of dose-adjusting gemfibrozil when it is given in combination with ritonavir in order to maximize the pharmacologic effects of gemfibrozil.
Study design
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Gemfibrozil PK without LPV/r | Sham comparator | Drug: GemfibrozilSubjects received a single 600 mg dose of gemfibrozil without concurrent lopinavir-ritonavir 400mg/100mg; this is the "control" arm of a crossover study design. |
| Gemfibrozil PK after 2 weeks of LPV/r | Experimental | Drug: Lopinavir/RitonavirSingle dose (600 mg) Gemfibrozil pharmacokinetics (i.e. plasma concentrations collected over time to calculate area under the concentration vs. time curve) assessed after 14.5 days of lopinavir/ritonavir (400/100 mg twice daily) administration. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Age of 18 to 65 years.
- Healthy by medical history and physical exam.
- Test HIV negative.
- Screening laboratory values within institutional normal range.
- Negative serum pregnancy test for females of child-bearing potential within 7 days prior to the initiation of LPV/r.
Key exclusion criteria (13 listed)
- Concomitant routine therapy with any prescription, over-the-counter, herbal, or holistic medications, including oral contraceptives for 30 days prior to study participation.
- Subjects taking oral contraceptives currently, or within 30 days prior to study initiation.
- Intermittent (PRN) use of acetaminophen, non-steroidal antiinflammatory medications (i.e. ibuprofen), and loperamide will be allowed during the study.
- Subjects will be allowed to take a multivitamin with minerals, or equivalent, once daily if they desire to do so.
- Inability to obtain venous access for sample collection.
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 |
|---|---|---|
| Lopinavir/RitonavirAlso: lopinavir/ritonavir = Kaletra(TM)lopinavir 400 mg + ritonavir 100 mg twice daily for 2 weeks | Drug | Gemfibrozil PK after 2 weeks of LPV/r |
| GemfibrozilAlso: gemfibrozil (Teva Pharmaceuticals)Control arm (no intervention used in this arm) | Drug | Gemfibrozil PK without LPV/r |
Primary outcome
Gemfibrozil Area Under the Concentration vs. Time Curve (AUC)
Time frame: 22 days per subject (approximately 1 year for entire study completion)
AUC (ng*hr/mL) of gemfibrozil when given as a 600 mg dose by itself compared to gemfibrozil AUC after 14.5 days of lopinavir-ritonavir (400mg/100mg) twice daily.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Sep 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 19648824Busse KH, Hadigan C, Chairez C, Alfaro RM, Formentini E, Kovacs JA, Penzak SR. Gemfibrozil concentrations are significantly decreased in the presence of lopinavir-ritonavir. J Acquir Immune Defic Syndr. 2009 Oct 1;52(2):235-9. doi: 10.1097/QAI.0b013e3181b0610e.
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Screening Protocol
Pain
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.
Scott R Penzak, Pharm.D. principal investigator
CC Pharmacy Department
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Lopinavir/Ritonavir and Gemfibrozil in people with Healthy Volunteers, run by National Institutes of Health Clinical Center (CC) at 1 site in United States.
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 7 inclusion and 13 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 26 Sep 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Apr 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Gemfibrozil Area Under the Concentration vs. Time Curve (AUC) (time frame: 22 days per subject (approximately 1 year for entire study completion)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00474201, which also lists 1 linked publication.
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 26 Sep 2016.