Genetics and HIV-1 Protease Inhibitors

Study Overview
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Brief Summary
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This study evaluated the blood levels of atazanavir according to a genetic makeup for CYP3A5 (cytochrome P450 3A5, an enzyme that metabolizes atazanavir). The hypothesis was that people with a slow-metabolizing genotype would have higher blood levels of atazanavir compared to people with the normal metabolizing genotype.

Official Title
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Genetic-determinants of Protease Inhibitor Pharmacology

Conditions
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HIV

Intervention / Treatment
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* Drug: Atazanavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 to 55 years Negative HIV screening antibody test CYP3A5 expressor status, race, and sex fit an enrollment opening. Exclusion Criteria: Pregnant or breast-feeding Medical history of hepatitis B or C, autoimmune disease, active malignancy, kidney disease including nephrolithiasis Organ dysfunction manifested by liver transaminases or serum creatinine >1.25 times the upper limit of normal, or any comprehensive metabolic test (except asymptomatic unconjugated hyperbilirubinemia), blood count, or lipid value > Grade I according to Division of AIDS (DAIDS) adverse drug event grading system (appendix). Medical history of arrhythmias (including atrial fibrillation, atrioventricular block, and/or pacemaker) Any QT interval abnormalities or other congenital arrhythmia syndromes on ECG or Any ECG abnormality that in the opinion of the investigators would preclude entry into the study. Medical history of any serious heart condition including: congestive heart failure, myopathies, coronary artery disease, or unexplained syncope. Medical history of bleeding disorders (i.e., hemophilia) Hyperlipidemia Any prescription, herbal, recreational, or over-the-counter medication contraindicated with ritonavir or atazanavir including: substrates/inhibitors/inducers of CYP3A/P-gp, cardio-active medication, or medications that alter the acid in the stomach. The study investigators will review each concurrent medication on a case-by-case basis. Inability to refrain from grapefruit or grapefruit juice during the study. Investigational drugs within the last 30 days. Active alcohol / recreational drug abuse, Inability to give informed consent. A body mass index below 18.5 or above 34.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CYP3A5 Expressors<br>A pre-screening genetic test determines CYP3A5 expressor status | Drug: Atazanavir<br>* Atazanavir 400mg once daily for 7 days followed by atazanavir 300mg plus ritonavir 100mg for 7 days<br>* Other names: Norvir;|
| Active Comparator: CYP3A5 Non-expressors<br>A pre-screening genetic test determines CYP3A5 non-expressor status | Drug: Atazanavir<br>* Atazanavir 400mg once daily for 7 days followed by atazanavir 300mg plus ritonavir 100mg for 7 days<br>* Other names: Norvir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Day 7 Atazanavir Oral Clearance | Measure atazanavir oral clearance in genetically-determined CYP3A5 expressors versus CYP3A5 non-expressors | Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Clinical Pharmacology, Pharmacogenomics, HIV