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.

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.

Inclusion Criteria:

1. Able and willing to give written informed consent.
2. Negative HIV-1 serology documented by any licensed ELISA test kit within 30 days prior to initiating study drug.
3. Men and women at least 18 but no more than 55 years of age at study entry.

4. Body mass index less than 30.

   Body mass index = (weight in kilograms)/(height in meters)2 OR Body mass index = [(weight in pounds)/(height in inches)2] X 703

5. Estimated creatinine clearance ≥ 50 mL/minute within 30 days prior to study entry, calculated by the Cockcroft-Gault method as follows:

   Men: creatinine clearance = [(140 - age) x (weight in kg)]/(72 x serum creatinine)

   Women: creatinine clearance = 0.85 x [(140 - age) x (weight in kg)]/(72 x serum creatinine)

6. Laboratory values obtained within 30 days prior to study entry:

   • Absolute neutrophil count (ANC) ≥ 1,000/mm3.
   • Hemoglobin ≥ 12.5 g/dL for males and ≥ 11.5 g/dL for females.
   • Platelet count ≥ 100,000/mm3.
   • AST (SGOT), ALT (SGPT), and total bilirubin within normal range.
   • Alkaline phosphatase less than or equal to 1.5 x upper limit of normal (ULN).
7. Female study volunteers of reproductive potential (defined as women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone surgical sterilization [e.g., hysterectomy, bilateral oophorectomy, or salpingotomy]) must have a negative serum or urine pregnancy test performed within 30 days before study entry.

8. All study volunteers must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization).

   If participating in sexual activity that could lead to pregnancy, all study volunteers must agree that AT LEAST ONE of the following reliable methods of contraception will be used while they are receiving protocol-specified medications and for 6 weeks after stopping the medications:

   • Condoms1 (male or female) with or without a spermicidal agent
   • Diaphragm or cervical cap with spermicide

   • IUD

     1. Condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV transmission.

   NOTE: Use of hormonal contraceptives is prohibited during this study because of the potential for drug interactions.

   All study volunteers who are not of reproductive potential (e.g., women who have been post-menopausal for at least 24 consecutive months, or women who have undergone surgical sterilization [e.g., hysterectomy and/or bilateral oophorectomy or salpingotomy], or men who have documented azoospermia) are eligible without requiring the use of contraception. Acceptable documentation of sterilization or menopause consists of written or oral documentation communicated by a clinician or a clinician's staff of one of the following:

   • Physician report/letter
   • Operative report or other source documentation in the patient record (a laboratory report of azoospermia is required to document successful vasectomy)
   • Discharge summary
   • Laboratory report of azoospermia
   • FSH measurement elevated into the menopausal range as established by the reporting laboratory.
9. Drug transporter gene ABCB1 position 3435 genotype either homozygous C/C or homozygous T/T.

Exclusion Criteria:

1. Within 14 days prior to entry, use of any medication that is metabolized by CYP3A or UGT1A1 (refer to manufacturers' package inserts for individual drugs).
2. Anticipated need to take any medication that is metabolized by CYP3A or UGT1A1 during the study.
3. Active drug use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
4. Inability to abstain from alcohol-containing beverages, grapefruit, and grapefruit juice for the duration of the study.
5. Serious illness that, in the opinion of the investigator, 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 such as trauma, congenital malformations or genetic disorders.
12. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.
13. ABCB1 position 3435 C/T heterozygosity during screening evaluation.