An interventional study of Lopinavir/Ritonavir and Gemfibrozil in Healthy Volunteers, sponsored by National Institutes of Health Clinical Center (CC). Completed at 1 site in United States. Open to participants aged 18 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2016-09-26.
Sponsored by National Institutes of Health Clinical Center (CC) · Not applicable and Interventional
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.
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.
National Institutes of Health Clinical Center (CC) is the lead sponsor of 367 studies on the registry; 27 are open to participants now.
Of its 22 completed or terminated interventional studies of FDA-regulated products, 18 (82%) have results posted.
Counted across the registry records on this site, refreshed daily.
EXCLUSION CRITERIA:
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
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
Also known as: lopinavir/ritonavir = Kaletra(TM)
Control arm (no intervention used in this arm)
Also known as: gemfibrozil (Teva Pharmaceuticals)
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.
Time frame: 22 days per subject (approximately 1 year for entire study completion)
Up to 30 healthy volunteers will be screened to enroll a total of 15 healthy volunteers. We will actively encourage participation of all ethnic groups and females. Recruitment of HIV-negative volunteers will be done through the normal volunteer office at NIH.
| Milestone | Gemfibrozil (GF) Alone Followed by GF+ Lopinavir-ritonavir |
|---|---|
| Started | 15 |
| Completed | 15 |
| Not completed | 0 |
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.
| ng*hr/mL | Gemfibrozil Alone (Control Group) | Gemfibrozil + Lopinavir-ritonavir |
|---|---|---|
| Gemfibrozil Area Under the Concentration vs. Time Curve (AUC) | 104 (90 to 118) | 62 (55 to 68) |
Collected over Adverse event data were collected throughout the study. Each subject particpiated in this study for approximately 22 days, while the entire duration of the study (collectively) for all 15 subjects was approximately one year.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Gemfibrozil (GF) Alone Followed by GF + Lopinavir-ritonavir | — | 0/15 (0%) | 0/15 (0%) |
| Age, Categorical(Participants) | Gemfibrozil (GF) Alone Followed by GF + Lopinavir-ritonavir |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 15 |
| >=65 years | 0 |
| Age, Continuous(years) | Gemfibrozil (GF) Alone Followed by GF + Lopinavir-ritonavir |
|---|---|
| Mean | 37 ± 10 |
| Sex: Female, Male(Participants) | Gemfibrozil (GF) Alone Followed by GF + Lopinavir-ritonavir |
|---|---|
| Female | 7 |
| Male | 8 |
| Region of Enrollment(participants) | Gemfibrozil (GF) Alone Followed by GF + Lopinavir-ritonavir |
|---|---|
| United States | 15 |
This study is completed, as verified in Mar 2012. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
National Institutes of Health Clinical Center (CC)