HIV Infections
Conditions
Keywords
Raltegravir, CSF, ABCB1 SNP, HIV/AIDS
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.
Interventions
DRUGRaltegravir
400mg orally every 12 hours for 7 days
Sponsors
Vanderbilt University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Penetration of Raltegravir (RGV) Into Cerebrospinal Fluid (CSF) Based on Plasma Area-under-the-curve. | Day 7 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Penetration of Raltegravir (RGV) Into Cerebrospinal Fluid (CSF) Based on Single Plasma Timepoint. | Day 7 | This outcome was the ratio of the 4-hour CSF concentration value (ng/mL) to the 4-hour plasma concentration value (ng/mL). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Raltegravir: 400mg Orally Every 12 Hours for 7 Days Raltegravir a single 400mg tablet taken orally every 12 hours for a total of 7 days. | 40 |
| Total | 40 |
Baseline characteristics
| Characteristic | Raltegravir: 400mg Orally Every 12 Hours for 7 Days |
|---|---|
| ABCB1 Genotype C/C Genotype | 20 participants |
| ABCB1 Genotype T/T Genotype | 20 participants |
| Age, Continuous | 34.5 years |
| Body Mass Index | 24.0 kilgrams/(meter squared) |
| Cerebrospinal Fluid Protein | 33 mg/dL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 40 Participants |
| Region of Enrollment United States | 40 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 20 Participants |
| Weight | 74.6 kilograms |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 40 |
| serious Total, serious adverse events | 0 / 40 |
Outcome results
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).
Time frame: Day 7
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Raltegravir: 400mg Orally Every 12 Hours for 7 Days (ABCB1 C/C | Penetration of Raltegravir (RGV) Into Cerebrospinal Fluid (CSF) Based on Plasma Area-under-the-curve. | 0.0066 1/h |
| Raltegravir: 400mg Orally Every 12 Hours for 7 Days (ABCB1 T/T | Penetration of Raltegravir (RGV) Into Cerebrospinal Fluid (CSF) Based on Plasma Area-under-the-curve. | 0.0070 1/h |
Comparison: The hypothesis was that the ratio of the 4-hour CSF concentration value to the partial plasma area-under-the-curve 0-4h value would differ between participants with ABCB1 C/C and T/T genotypes.p-value: 0.43Wilcoxon (Mann-Whitney)
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).
Time frame: Day 7
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Raltegravir: 400mg Orally Every 12 Hours for 7 Days (ABCB1 C/C | Penetration of Raltegravir (RGV) Into Cerebrospinal Fluid (CSF) Based on Single Plasma Timepoint. | 0.028 ratio |
| Raltegravir: 400mg Orally Every 12 Hours for 7 Days (ABCB1 T/T | Penetration of Raltegravir (RGV) Into Cerebrospinal Fluid (CSF) Based on Single Plasma Timepoint. | 0.021 ratio |
Comparison: We explored post-hoc whether the ratio of the 4-hour CSF concentration value to the 2-hour plasma concentration differs between participants with ABCB1 C/C and T/T genotypes.p-value: 0.43Wilcoxon (Mann-Whitney)