Genetic Predictors of Raltegravir Penetration Into Cerebrospinal Fluid

HIV Infections Clinical Trial

Official title:

Genetic Predictors of Raltegravir Penetration Into Cerebrospinal Fluid

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00729924
• Other study ID #: 080536
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: August 4, 2008
• Last updated: March 2, 2015
• Start date: August 2008
• Est. completion date: August 2011

Study information

• Verified date: March 2015
• Source: Vanderbilt University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: August 2011
• Est. primary completion date: February 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Raltegravir
400mg orally every 12 hours for 7 days

Locations

Country	Name	City	State
United States	Vanderbilt Therapeutics Clinical Research Site	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University

Country where clinical trial is conducted

United States, 

References & Publications (1)

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.pon — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No