HIVNCT01214486
Measurement of Plasma and Intracellular Concentrations of Raltegravir
A study testing Raltegravir in people with HIV, run by University of Nebraska at 1 site in United States.
Trial summary
The primary purpose of this study is to analyze and compare plasma and intracellular concentrations of Raltegravir (RAL) in blood plasma and in peripheral blood mononuclear cells, using high performance liquid chromatography (HPLC). Read more about this study
- Who is it for?
- Ages 19 years and older
- Conditions the study is for
- HIV
- What is being tested?
- Raltegravir
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Oct 2010to 30 Jun 2011
- Phase
- Interventional
- 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 19 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Be of age greater than or equal to 19 years
- Have documented HIV
- Be taking RAL for at least 7 days
Who cannot join
- Any acute intercurrent illness that might interfere with the interpretation of the study
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Nebraska Medical Center
Omaha, Nebraska, 68198
About this study
Official title: Measurement of Plasma and Intracellular Concentrations of Raltegravir in Patients Infected With Human Immunodeficiency Virus
The primary purpose of this study is to analyze and compare plasma and intracellular concentrations of Raltegravir (RAL) in blood plasma and in peripheral blood mononuclear cells, using high performance liquid chromatography (HPLC).
Read the detailed description
Integrase strand transfer inhibitors are one of the newest class of antiretroviral drugs. This class of drugs inhibit the catalytic activity of HIV-1 integrase, an HIV-1-encoded enzyme required for viral replication [1]. Inhibition of integrase prevents covalent insertion of unintegrated, linear HIV-1 DNA into the host cell genome, therefore preventing the formation of HIV-1 provirus. RAL, the first agent in its class, was initially approved in 2007 for use in patients harboring drug-resistant HIV [2]. More recently, the FDA has expanded the indication for RAL use in HIV-infected patients who are antiretroviral naïve [3]. The currently approved dose is 400 mg twice daily. The RAL area-under-the-curve (AUC) and Cmax increase in a dose-dependent fashion over the range of 100 mg to 1,600 mg. With twice-daily dosing, PK steady state is achieved within approximately the first 2 days. Considerable variability was observed in the PK of raltegravir in clinical trials. In clinical trial participants receiving twice-daily RAL 400 mg, drug exposures were characterized by a geometric mean AUC within the first 12 hours of 14.3 mcM(hr) and a plasma concentration at 12 hours of 142 nM [3]. RAL at concentrations of 6 to 50 nM resulted in 95% inhibition (EC95) of viral spread in mitogen-activated human peripheral blood mononuclear cells (PBMCs) infected with diverse, primary clinical isolates of HIV-1, including isolates resistant to reverse transcriptase inhibitors and protease inhibitors (PIs).
The absolute bioavailability of RAL has not been established. RAL is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 mcM. The apparent terminal half-life of RAL is approximately 9 hours, with a shorter alpha-phase half-life (about 1 hour), accounting for much of the AUC. Determination of drug levels to guide treatment of HIV infection is available for protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) but is not yet considered standard of care [4,5]. RAL is associated with potent performance against HIV in treatment-naïve patients and those with limited treatment options, potentially because of its binding interaction with the HIV preintegration complex. When RAL binds to the complex, the drug dissociates at a rate slower than the half-life of the complex itself, which makes binding essentially irreversible. Thus, the efficacy of RAL may be dependent on intracellular binding levels of the drug to the preintegration complex, rather than on the plasma concentrations of RAL. Because of this, we postulate that intracellular concentrations of RAL are more likely to correlate with biological activity against HIV. Moreover, if pharmacokinetic behavior can be predicted, and depending on the trough concentrations observed, the drug might be suitable for different dosing approaches including once a day administration. This would create more flexibility for patients, and the chance to improve adherence.
- Conditions
- HIV
- Being tested
- Raltegravir
- Keywords
- HIV, RAL, Raltegravir, Isentress, Pharmacokinetics
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RaltegravirDrug
Also called RAL, Isentress
Subjects should be on RAL 400mg twice daily at least 1 week. Subjects will be asked to come to the Specialty Clinic at two different points on the same day: at either 2, 4 or 6 hours after taking the drug, and at 10 or 12 hours after taking the drug. After completion of the first part of the study, subjects whose viral load is below the limit of detection (HIV RNA < 50 copies/mL) will be asked to switch to once a day RAL dosing (i.e. 800 mg once a day). Once the a subject has taken RAL once a day for at least three consecutive days, s/he will be asked to come to the Specialty Clinic at two different points in the same day to obtain blood by venous puncture. Blood will be obtained 2 or 4 hours after the dose and at 20-24 hours after the dose.
| Study group | Role | What they receive |
|---|---|---|
| Raltegravir | Experimental | Not described Receives: Drug: Raltegravir |
What is being measured
The primary outcome is the main question the study is designed to answer.
Concentrations of RAL in blood cells.
Analyze and compare plasma and intracellular concentrations of RAL in blood plasma and in peripheral blood mononuclear cells, using high performance liquid chromatography (HPLC).
Measured: one month
Concentrations of RAL in blood plasma.
Analyze and compare plasma and intracellular concentrations of RAL in blood plasma and in peripheral blood mononuclear cells, using high performance liquid chromatography (HPLC).
Measured: one month
Secondary outcomes (4)
Pharmacokinetic variability of plasma concentrations of the drug.
To determine the pharmacokinetic variability of plasma and intracellular concentrations of the drug.
Measured: one month
Pharmacokinetic variability of intracellular concentrations of the drug.
To determine the pharmacokinetic variability of plasma and intracellular concentrations of the drug.
Measured: one month
Trough concentrations of the drug when dosed twice daily versus once daily.
To compare pharmacokinetics of the drug when dosed twice daily versus once daily.
Measured: one month
Pharmacokinetics of the drug when dosed twice daily versus once daily.
To compare pharmacokinetics of the drug when dosed twice daily versus once daily.
Measured: One month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Oct 2010 (estimated)
- Study start1 Oct 2010
- Primary completion30 Apr 2011
- Study completion30 Jun 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for HIVStudies of the same condition, open and under way.
- More trials run by University of NebraskaThe 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 N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Nebraska
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Uriel Sandkovsky, MD, University of Nebraska
- Investigators
- Uriel S Sandkovsky, MD, Principal investigator, University of Nebraska
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01214486
- Sponsor's protocol ID
- 506-10-FB
- Status last verified
- Aug 2017
- First submitted
- 28 Sep 2010
- Last updated
- 21 Aug 2017
- Results posted
- No
- Data monitoring committee
- No
Publications
Thompson MA, Aberg JA, Cahn P, Montaner JS, Rizzardini G, Telenti A, Gatell JM, Gunthard HF, Hammer SM, Hirsch MS, Jacobsen DM, Reiss P, Richman DD, Volberding PA, Yeni P, Schooley RT; International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010 Jul 21;304(3):321-33. doi: 10.1001/jama.2010.1004.
PubMed 20639566Hicks C, Gulick RM. Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis. 2009 Apr 1;48(7):931-9. doi: 10.1086/597290.
PubMed 192319803. http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf
de Maat MM, Huitema AD, Mulder JW, Meenhorst PL, van Gorp EC, Mairuhu AT, Beijnen JH. Subtherapeutic antiretroviral plasma concentrations in routine clinical outpatient HIV care. Ther Drug Monit. 2003 Jun;25(3):367-73. doi: 10.1097/00007691-200306000-00018.
PubMed 12766566Powderly WG, Saag MS, Chapman S, Yu G, Quart B, Clendeninn NJ. Predictors of optimal virological response to potent antiretroviral therapy. AIDS. 1999 Oct 1;13(14):1873-80. doi: 10.1097/00002030-199910010-00009.
PubMed 10513645Shah VP, Midha KK, Findlay JW, Hill HM, Hulse JD, McGilveray IJ, McKay G, Miller KJ, Patnaik RN, Powell ML, Tonelli A, Viswanathan CT, Yacobi A. Bioanalytical method validation--a revisit with a decade of progress. Pharm Res. 2000 Dec;17(12):1551-7. doi: 10.1023/a:1007669411738. No abstract available.
PubMed 11303967Viswanathan CT, Bansal S, Booth B, DeStefano AJ, Rose MJ, Sailstad J, Shah VP, Skelly JP, Swann PG, Weiner R. Quantitative bioanalytical methods validation and implementation: best practices for chromatographic and ligand binding assays. Pharm Res. 2007 Oct;24(10):1962-73. doi: 10.1007/s11095-007-9291-7. Epub 2007 Apr 26.
PubMed 17458684King T, Bushman L, Anderson PL, Delahunty T, Ray M, Fletcher CV. Quantitation of zidovudine triphosphate concentrations from human peripheral blood mononuclear cells by anion exchange solid phase extraction and liquid chromatography-tandem mass spectroscopy; an indirect quantitation methodology. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Feb 2;831(1-2):248-57. doi: 10.1016/j.jchromb.2005.12.033. Epub 2006 Jan 10.
PubMed 16412710Remmel RP, Kawle SP, Weller D, Fletcher CV. Simultaneous HPLC assay for quantification of indinavir, nelfinavir, ritonavir, and saquinavir in human plasma. Clin Chem. 2000 Jan;46(1):73-81.
PubMed 10620574
Study at a glance
From the registry record, last updated by the sponsor on 21 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Measurement of Plasma and Intracellular Concentrations of Raltegravir in Patients Infected With Human Immunodeficiency Virus
- ClinicalTrials.gov ID
- NCT01214486
- Acronym / sponsor ID
- 506-10-FB
- Conditions
- HIV
- Keywords
- HIV, RAL, Raltegravir, Isentress, Pharmacokinetics
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- University of NebraskaUniversity, hospital or other
- Study start
- 1 Oct 2010 (actual)
- Primary completion
- 30 Apr 2011 (actual)
- Study completion
- 30 Jun 2011 (actual)
- First posted
- 5 Oct 2010 (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 primary purpose of this study is to analyze and compare plasma and intracellular concentrations of Raltegravir (RAL) in blood plasma and in peripheral blood mononuclear cells, using high performance liquid chromatography (HPLC).
Detailed description
Integrase strand transfer inhibitors are one of the newest class of antiretroviral drugs. This class of drugs inhibit the catalytic activity of HIV-1 integrase, an HIV-1-encoded enzyme required for viral replication [1]. Inhibition of integrase prevents covalent insertion of unintegrated, linear HIV-1 DNA into the host cell genome, therefore preventing the formation of HIV-1 provirus. RAL, the first agent in its class, was initially approved in 2007 for use in patients harboring drug-resistant HIV [2]. More recently, the FDA has expanded the indication for RAL use in HIV-infected patients who are antiretroviral naïve [3]. The currently approved dose is 400 mg twice daily. The RAL area-under-the-curve (AUC) and Cmax increase in a dose-dependent fashion over the range of 100 mg to 1,600 mg. With twice-daily dosing, PK steady state is achieved within approximately the first 2 days. Considerable variability was observed in the PK of raltegravir in clinical trials. In clinical trial participants receiving twice-daily RAL 400 mg, drug exposures were characterized by a geometric mean AUC within the first 12 hours of 14.3 mcM(hr) and a plasma concentration at 12 hours of 142 nM [3]. RAL at concentrations of 6 to 50 nM resulted in 95% inhibition (EC95) of viral spread in mitogen-activated human peripheral blood mononuclear cells (PBMCs) infected with diverse, primary clinical isolates of HIV-1, including isolates resistant to reverse transcriptase inhibitors and protease inhibitors (PIs).
The absolute bioavailability of RAL has not been established. RAL is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 mcM. The apparent terminal half-life of RAL is approximately 9 hours, with a shorter alpha-phase half-life (about 1 hour), accounting for much of the AUC. Determination of drug levels to guide treatment of HIV infection is available for protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) but is not yet considered standard of care [4,5]. RAL is associated with potent performance against HIV in treatment-naïve patients and those with limited treatment options, potentially because of its binding interaction with the HIV preintegration complex. When RAL binds to the complex, the drug dissociates at a rate slower than the half-life of the complex itself, which makes binding essentially irreversible. Thus, the efficacy of RAL may be dependent on intracellular binding levels of the drug to the preintegration complex, rather than on the plasma concentrations of RAL. Because of this, we postulate that intracellular concentrations of RAL are more likely to correlate with biological activity against HIV. Moreover, if pharmacokinetic behavior can be predicted, and depending on the trough concentrations observed, the drug might be suitable for different dosing approaches including once a day administration. This would create more flexibility for patients, and the chance to improve adherence.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Raltegravir | Experimental | Drug: Raltegravir |
Who may qualify
- Ages
- 19 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Be of age greater than or equal to 19 years
- Have documented HIV
- Be taking RAL for at least 7 days
Key exclusion criteria (1 listed)
- Any acute intercurrent illness that might interfere with the interpretation of the study
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 |
|---|---|---|
| RaltegravirAlso: RAL, IsentressSubjects should be on RAL 400mg twice daily at least 1 week. Subjects will be asked to come to the Specialty Clinic at two different points on the same day: at either 2, 4 or 6 hours after taking the drug, and at 10 or 12 hours after taking the drug. After completion of the first part of the study, subjects whose viral load is below the limit of detection (HIV RNA < 50 copies/mL) will be asked to switch to once a day RAL dosing (i.e. 800 mg once a day). Once the a subject has taken RAL once a day for at least three consecutive days, s/he will be asked to come to the Specialty Clinic at two different points in the same day to obtain blood by venous puncture. Blood will be obtained 2 or 4 hours after the dose and at 20-24 hours after the dose. | Drug | Raltegravir |
Primary outcome
Concentrations of RAL in blood cells.
Time frame: one month
Analyze and compare plasma and intracellular concentrations of RAL in blood plasma and in peripheral blood mononuclear cells, using high performance liquid chromatography (HPLC).
Concentrations of RAL in blood plasma.
Time frame: one month
Analyze and compare plasma and intracellular concentrations of RAL in blood plasma and in peripheral blood mononuclear cells, using high performance liquid chromatography (HPLC).
4 secondary outcomes
Pharmacokinetic variability of plasma concentrations of the drug.
Time frame: one month
Pharmacokinetic variability of intracellular concentrations of the drug.
Time frame: one month
Trough concentrations of the drug when dosed twice daily versus once daily.
Time frame: one month
Pharmacokinetics of the drug when dosed twice daily versus once daily.
Time frame: One month
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 21 Aug 2017.
- Background: PubMed 20639566Thompson MA, Aberg JA, Cahn P, Montaner JS, Rizzardini G, Telenti A, Gatell JM, Gunthard HF, Hammer SM, Hirsch MS, Jacobsen DM, Reiss P, Richman DD, Volberding PA, Yeni P, Schooley RT; International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010 Jul 21;304(3):321-33. doi: 10.1001/jama.2010.1004.
- Background: PubMed 19231980Hicks C, Gulick RM. Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis. 2009 Apr 1;48(7):931-9. doi: 10.1086/597290.
- Background3. http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf
- Background: PubMed 12766566de Maat MM, Huitema AD, Mulder JW, Meenhorst PL, van Gorp EC, Mairuhu AT, Beijnen JH. Subtherapeutic antiretroviral plasma concentrations in routine clinical outpatient HIV care. Ther Drug Monit. 2003 Jun;25(3):367-73. doi: 10.1097/00007691-200306000-00018.
- Background: PubMed 10513645Powderly WG, Saag MS, Chapman S, Yu G, Quart B, Clendeninn NJ. Predictors of optimal virological response to potent antiretroviral therapy. AIDS. 1999 Oct 1;13(14):1873-80. doi: 10.1097/00002030-199910010-00009.
- Background: PubMed 11303967Shah VP, Midha KK, Findlay JW, Hill HM, Hulse JD, McGilveray IJ, McKay G, Miller KJ, Patnaik RN, Powell ML, Tonelli A, Viswanathan CT, Yacobi A. Bioanalytical method validation--a revisit with a decade of progress. Pharm Res. 2000 Dec;17(12):1551-7. doi: 10.1023/a:1007669411738. No abstract available.
- Background: PubMed 17458684Viswanathan CT, Bansal S, Booth B, DeStefano AJ, Rose MJ, Sailstad J, Shah VP, Skelly JP, Swann PG, Weiner R. Quantitative bioanalytical methods validation and implementation: best practices for chromatographic and ligand binding assays. Pharm Res. 2007 Oct;24(10):1962-73. doi: 10.1007/s11095-007-9291-7. Epub 2007 Apr 26.
- Background: PubMed 16412710King T, Bushman L, Anderson PL, Delahunty T, Ray M, Fletcher CV. Quantitation of zidovudine triphosphate concentrations from human peripheral blood mononuclear cells by anion exchange solid phase extraction and liquid chromatography-tandem mass spectroscopy; an indirect quantitation methodology. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Feb 2;831(1-2):248-57. doi: 10.1016/j.jchromb.2005.12.033. Epub 2006 Jan 10.
- Background: PubMed 10620574Remmel RP, Kawle SP, Weller D, Fletcher CV. Simultaneous HPLC assay for quantification of indinavir, nelfinavir, ritonavir, and saquinavir in human plasma. Clin Chem. 2000 Jan;46(1):73-81.
- University of Nebraska Medical Center HIV ClinicLink provided by the sponsor.
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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.
Uriel S Sandkovsky, MD principal investigator
University of Nebraska
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Raltegravir in people with HIV, run by University of Nebraska 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 3 inclusion and 1 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 21 Aug 2017. 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. 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?
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?
Concentrations of RAL in blood cells. (time frame: one month). The study lists 2 primary outcomes in all. 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 NCT01214486, which also lists 9 linked publications.
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 21 Aug 2017; AzTrials last refreshed its copy on 8 Nov 2026.