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Drug Interaction Study of Lopinavir/Ritonavir and Gemfibrozil (GEM-PK)

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ClinicalTrials.gov Identifier: NCT00474201
Recruitment Status : Completed
First Posted : May 16, 2007
Results First Posted : April 9, 2012
Last Update Posted : September 26, 2016
Sponsor:
Information provided by (Responsible Party):
Scott Penzak, Pharm.D., National Institutes of Health Clinical Center (CC)

Study Description
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Brief 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. 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.


Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Lopinavir/Ritonavir Drug: Gemfibrozil Not Applicable

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
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Official Title: The Influence of Lopinavir/Ritonavir on Gemfibrozil Pharmacokinetics in Healthy Volunteers
Study Start Date : May 2007
Actual Primary Completion Date : July 2008
Actual Study Completion Date : July 2008

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U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Sham Comparator: Gemfibrozil PK without LPV/r
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.
 Drug: Gemfibrozil
Control arm (no intervention used in this arm)
Other Name: gemfibrozil (Teva Pharmaceuticals)
Experimental: Gemfibrozil PK after 2 weeks of LPV/r
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.
 Drug: Lopinavir/Ritonavir
lopinavir 400 mg + ritonavir 100 mg twice daily for 2 weeks
Other Name: lopinavir/ritonavir = Kaletra(TM)


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

INCLUSION CRITERIA:

  • 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.

EXCLUSION CRITERIA:

  • 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.
  • 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.
Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00474201


Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institutes of Health Clinical Center (CC)
Investigators
Principal Investigator: Scott R Penzak, Pharm.D. CC Pharmacy Department
More Information
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

Responsible Party: Scott Penzak, Pharm.D., Director, Clinical Pharmacokinetics research Laboratory, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00474201     History of Changes
Other Study ID Numbers: 070149
07-CC-0149 CL006000-01 CC ( Other Identifier: Clinical Center Z number )
First Posted: May 16, 2007    Key Record Dates
Results First Posted: April 9, 2012
Last Update Posted: September 26, 2016
Last Verified: March 2012

Keywords provided by Scott Penzak, Pharm.D., National Institutes of Health Clinical Center (CC):
Pharmacokinetic
HIV
Drug-Drug Interaction
Lopinavir/Ritonavir
 Gemfibrozil
Healthy Volunteer
HV

Additional relevant MeSH terms:
Ritonavir
Lopinavir
Gemfibrozil
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
 Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Cytochrome P-450 CYP2C8 Inhibitors