Clinical trial NCT00729924: Genetic Predictors of Raltegravir Penetration Into Cerebrospinal Fluid
Official title: Genetic Predictors of Raltegravir Penetration Into Cerebrospinal Fluid
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: HIV Infections
Keywords: Raltegravir
CSF
ABCB1 SNP
HIV/AIDS
Lead sponsor: Vanderbilt University
Sponsor class: OTHER
First posted: 2008-08-08
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Penetration of Raltegravir (RGV) Into Cerebrospinal Fluid (CSF) Based on Plasma Area-under-the-curve.
timeFrame: Day 7
Secondary outcomes:
measure: Penetration of Raltegravir (RGV) Into Cerebrospinal Fluid (CSF) Based on Single Plasma Timepoint.
timeFrame: Day 7
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt Therapeutics Clinical Research Site
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: David W Haas, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.