Genetic Predictors of Raltegravir Penetration Into Cerebrospinal Fluid

Study Overview
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Brief Summary
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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
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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.

Official Title
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Genetic Predictors of Raltegravir Penetration Into Cerebrospinal Fluid

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Raltegravir


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Able to give informed consent. Negative HIV-1 serology. At least 18 but no more than 55 years of age. Body mass index <30. Estimated creatinine clearance ≥ 50 mL/minute within 30 days prior to study entry. 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. Female study volunteers of reproductive potential must have a negative serum or urine pregnancy test performed within 30 days before study entry. Must agree not to participate in a conception process. Drug transporter gene ABCB1 position 3435 genotype C/C or T/T. Exclusion criteria: Use of any medication that is metabolized by CYP3A or UGT1A1. Anticipated need to take any medication that is metabolized by CYP3A or UGT1A1 during the study. Active drug use or dependence. Inability to abstain from alcohol-containing beverages, grapefruit, and grapefruit juice. Serious illness that would interfere with study participation. Hospitalization for any reason or therapy for serious illness within 14 days prior to study entry. History of hypersensitivity to study drug or its formulation. 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. Breast-feeding. Evidence of CNS infection or space occupying lesion by history or physical examination. History of significant CNS disorder. Prisoners or subjects who are compulsorily detained. ABCB1 position 3435 C/T heterozygosity.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Raltegravir, CSF, ABCB1 SNP, HIV/AIDS