Measurement of Plasma and Intracellular Concentrations of Raltegravir

NCT ID: NCT01214486

Last Updated: 2017-08-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-10-01
• Study Completion Date: 2011-06-30

Brief 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).

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Raltegravir

Group Type: EXPERIMENTAL

Raltegravir

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

RAL; Isentress

Eligibility 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

• Minimum Eligible Age: 19 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Nebraska

OTHER

Sponsor Role: lead

Responsible Party

Uriel Sandkovsky, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Uriel S Sandkovsky, MD

Role: PRINCIPAL_INVESTIGATOR

University of Nebraska

Locations

University of Nebraska Medical Center

Omaha, Nebraska, United States

Countries

United States

References

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Related Links

http://www.unmc.edu/hiv

University of Nebraska Medical Center HIV Clinic

Other Identifiers

506-10-FB

Identifier Type: -

Identifier Source: org_study_id