Measurement of Plasma and Intracellular Concentrations of Raltegravir

The recruitment status of this study is unknown because the information has not been verified recently.
Verified November 2010 by University of Nebraska.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
University of Nebraska
ClinicalTrials.gov Identifier:
NCT01214486
First received: September 28, 2010
Last updated: November 12, 2010
Last verified: November 2010
  Purpose

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).


Condition Intervention
HIV
Drug: Raltegravir

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Measurement of Plasma and Intracellular Concentrations of Raltegravir in Patients Infected With Human Immunodeficiency Virus

Resource links provided by NLM:


Further study details as provided by University of Nebraska:

Primary Outcome Measures:
  • Concentrations of RAL in blood cells. [ Time Frame: one month ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Analyze and compare plasma and intracellular concentrations of RAL in blood plasma and in peripheral blood mononuclear cells, using high performance liquid chromatography (HPLC).


Secondary Outcome Measures:
  • Pharmacokinetic variability of plasma concentrations of the drug. [ Time Frame: one month ] [ Designated as safety issue: No ]
    To determine the pharmacokinetic variability of plasma and intracellular concentrations of the drug.

  • Pharmacokinetic variability of intracellular concentrations of the drug. [ Time Frame: one month ] [ Designated as safety issue: No ]
    To determine the pharmacokinetic variability of plasma and intracellular concentrations of the drug.

  • Trough concentrations of the drug when dosed twice daily versus once daily. [ Time Frame: one month ] [ Designated as safety issue: No ]
    To compare pharmacokinetics of the drug when dosed twice daily versus once daily.

  • Pharmacokinetics of the drug when dosed twice daily versus once daily. [ Time Frame: One month ] [ Designated as safety issue: No ]
    To compare pharmacokinetics of the drug when dosed twice daily versus once daily.


Estimated Enrollment: 25
Study Start Date: October 2010
Estimated Study Completion Date: June 2011
Estimated Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Raltegravir Drug: Raltegravir
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.
Other Names:
  • RAL
  • Isentress

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.

  Eligibility

Ages Eligible for Study:   19 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Be of age greater than or equal to 19 years
  • Have documented HIV
  • Be taking RAL for at least 7 days

Exclusion Criteria:

  • Any acute intercurrent illness that might interfere with the interpretation of the study
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01214486

Contacts
Contact: Frances J Van Meter, APRN 402-559-8163 fvanmete@unmc.edu
Contact: Jennifer L O'Neill, RN,BSN 402-559-4408 jloneill@unmc.edu

Locations
United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
Contact: Frances J Van Meter, APRN    402-559-8163    fvanmete@unmc.edu   
Contact: Jennifer L O'Neill, RN,BSN    402-559-4408    jloneill@unmc.edu   
Principal Investigator: Uriel S Sandkovsky, MD         
Sub-Investigator: Susan Swindells, MBBS         
Sponsors and Collaborators
University of Nebraska
Investigators
Principal Investigator: Uriel S Sandkovsky, MD University of Nebraska
  More Information

Additional Information:
Publications:

Responsible Party: Uriel S. Sandkovsky, MD/Principal Investigator, University of Nebraska Medical Center
ClinicalTrials.gov Identifier: NCT01214486     History of Changes
Other Study ID Numbers: 506-10-FB
Study First Received: September 28, 2010
Last Updated: November 12, 2010
Health Authority: United States: Institutional Review Board

Keywords provided by University of Nebraska:
HIV
RAL
Raltegravir
Isentress
Pharmacokinetics

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases

ClinicalTrials.gov processed this record on April 23, 2014