Measurement of Plasma and Intracellular Concentrations of Raltegravir

August 16, 2017 updated by: Uriel Sandkovsky, MD, University of Nebraska

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

12

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Nebraska
      • Omaha, Nebraska, United States, 68198
        • University of Nebraska Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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:
  • Isentress
  • RAL

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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).
one month
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).
one month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacokinetic variability of plasma concentrations of the drug.
Time Frame: one month
To determine the pharmacokinetic variability of plasma and intracellular concentrations of the drug.
one month
Pharmacokinetic variability of intracellular concentrations of the drug.
Time Frame: one month
To determine the pharmacokinetic variability of plasma and intracellular concentrations of the drug.
one month
Trough concentrations of the drug when dosed twice daily versus once daily.
Time Frame: one month
To compare pharmacokinetics of the drug when dosed twice daily versus once daily.
one month
Pharmacokinetics of the drug when dosed twice daily versus once daily.
Time Frame: One month
To compare pharmacokinetics of the drug when dosed twice daily versus once daily.
One month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Nebraska

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

October 1, 2010

Primary Completion (ACTUAL)

April 30, 2011

Study Completion (ACTUAL)

June 30, 2011

Study Registration Dates

First Submitted

September 28, 2010

First Submitted That Met QC Criteria

October 1, 2010

First Posted (ESTIMATE)

October 5, 2010

Study Record Updates

Last Update Posted (ACTUAL)

August 21, 2017

Last Update Submitted That Met QC Criteria

August 16, 2017

Last Verified

August 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 506-10-FB

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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