Genetic Predictors of Raltegravir Penetration Into Cerebrospinal Fluid

This study is being done to find out how much of the drug raltegravir (RGV) gets into cerebrospinal fluid (CSF), compared to how much get into the blood and to find out if normal changes in a certain gene in your body affects how much RGV gets into the CSF.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Raltegravir

Detailed Description

The multidrug efflux transporter P-glycoprotein (P-gp) is expressed in the blood-brain barrier where it limits entry of substrate drugs into the central nervous system. Raltegravir (MK-0158), a new HIV-1 integrase inhibitor and potentially major addition to the therapeutic armamentarium against HIV, is a substrate for P-gp. Studies are warranted to elucidate the relevance of P-gp transport for raltegravir in the central nervous system.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37204
      • Vanderbilt Therapeutics Clinical Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Able to give informed consent.
2. Negative HIV-1 serology.
3. At least 18 but no more than 55 years of age.
4. Body mass index <30.
5. Estimated creatinine clearance ≥ 50 mL/minute within 30 days prior to study entry.

6. Within 30 days prior to study entry:

   • Absolute neutrophil count ≥ 1,000/mm3.
   • Hemoglobin ≥ 12.5 g/dL for males and ≥ 11.5 g/dL for females.
   • Platelet count ≥ 100,000/mm3.
   • AST, ALT, and total bilirubin within normal range.
   • Alkaline phosphatase < or = 1.5 x upper limit of normal.
7. Female study volunteers of reproductive potential must have a negative serum or urine pregnancy test performed within 30 days before study entry.
8. Must agree not to participate in a conception process.
9. Drug transporter gene ABCB1 position 3435 genotype C/C or T/T.

Exclusion criteria:

1. Use of any medication that is metabolized by CYP3A or UGT1A1.
2. Anticipated need to take any medication that is metabolized by CYP3A or UGT1A1 during the study.
3. Active drug use or dependence.
4. Inability to abstain from alcohol-containing beverages, grapefruit, and grapefruit juice.
5. Serious illness that would interfere with study participation.
6. Hospitalization for any reason or therapy for serious illness within 14 days prior to study entry.
7. History of hypersensitivity to study drug or its formulation.
8. As determined by the investigator, a significant active or previous history of cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, or immunologic disease(s). This is inclusive of chronic illnesses such as hypertension, coronary artery disease, arthritis, diabetes, any chronic gastrointestinal conditions that may affect drug absorption, etc.
9. Breast-feeding.
10. Evidence of CNS infection or space occupying lesion by history or physical examination.
11. History of significant CNS disorder.
12. Prisoners or subjects who are compulsorily detained.
13. ABCB1 position 3435 C/T heterozygosity.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open label oral raltegravir; Raltegravir a single 400 mg pill taken orally every 12 hours for a total of 7 days.	Drug: Raltegravir; 400mg orally every 12 hours for 7 days; Other Names: MK-0518

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Penetration of Raltegravir (RGV) Into Cerebrospinal Fluid (CSF) Based on Plasma Area-under-the-curve.	The primary outcome for this study was the ratio of the 4-hour CSF concentration value (ng/mL) to the partial plasma area-under-the-curve 0-4h value (h*ng/mL).	Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Penetration of Raltegravir (RGV) Into Cerebrospinal Fluid (CSF) Based on Single Plasma Timepoint.	This outcome was the ratio of the 4-hour CSF concentration value (ng/mL) to the 4-hour plasma concentration value (ng/mL).	Day 7

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Investigators: Principal Investigator: David W Haas, MD, Vanderbilt University Medical Center

Publications and helpful links

General Publications

• Johnson DH, Sutherland D, Acosta EP, Erdem H, Richardson D, Haas DW. Genetic and non-genetic determinants of raltegravir penetration into cerebrospinal fluid: a single arm pharmacokinetic study. PLoS One. 2013 Dec 11;8(12):e82672. doi: 10.1371/journal.pone.0082672. eCollection 2013.

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): February 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: August 4, 2008
• First Submitted That Met QC Criteria: August 7, 2008
• First Posted (Estimate): August 8, 2008

Study Record Updates

• Last Update Posted (Estimate): March 3, 2015
• Last Update Submitted That Met QC Criteria: March 2, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: HIV/AIDS; CSF; Raltegravir; ABCB1 SNP
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Raltegravir Potassium
• Other Study ID Numbers: 080536