Measurement of Plasma and Intracellular Concentrations of Raltegravir

HIV Clinical Trial

Official title:

Measurement of Plasma and Intracellular Concentrations of Raltegravir in Patients Infected With Human Immunodeficiency Virus

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01214486
• Other study ID #: 506-10-FB
• Status: Completed
• Phase: N/A
• First received: September 28, 2010
• Last updated: August 16, 2017
• Start date: October 1, 2010
• Est. completion date: June 30, 2011

Study information

• Verified date: August 2017
• Source: University of Nebraska
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: June 30, 2011
• Est. primary completion date: April 30, 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

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

Related Conditions & MeSH terms

• HIV

Intervention

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.

Locations

Country	Name	City	State
United States	University of Nebraska Medical Center	Omaha	Nebraska

Sponsors (1)

Lead Sponsor	Collaborator
University of Nebraska

Country where clinical trial is conducted

United States, 

References & Publications (9)

3. 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. — View Citation

Hicks 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. Review. — View Citation

King 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. Epub 2006 Jan 10. — View Citation

Powderly 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. — View Citation

Remmel 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. — View Citation

Shah 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. — View Citation

Thompson MA, Aberg JA, Cahn P, Montaner JS, Rizzardini G, Telenti A, Gatell JM, Günthard 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. — View Citation

Viswanathan 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. Epub 2007 Apr 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	one month
Primary	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).	one month
Secondary	Pharmacokinetic variability of plasma concentrations of the drug.	To determine the pharmacokinetic variability of plasma and intracellular concentrations of the drug.	one month
Secondary	Pharmacokinetic variability of intracellular concentrations of the drug.	To determine the pharmacokinetic variability of plasma and intracellular concentrations of the drug.	one month
Secondary	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.	one month
Secondary	Pharmacokinetics of the drug when dosed twice daily versus once daily.	To compare pharmacokinetics of the drug when dosed twice daily versus once daily.	One month

External Links

•   University of Nebraska Medical Center HIV Clinic