HIV
Conditions
Keywords
Pharmacokinetics, Clinical Pharmacology, Pharmacogenomics, HIV
Brief summary
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.
Interventions
DRUGAtazanavir
Atazanavir 400mg once daily for 7 days followed by atazanavir 300mg plus ritonavir 100mg for 7 days
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
University of Colorado, Denver
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Day 7 Atazanavir Oral Clearance | Day 7 | Measure atazanavir oral clearance in genetically-determined CYP3A5 expressors versus CYP3A5 non-expressors |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CYP3A5 Expressors A pre-screening genetic test determines CYP3A5 expressor status
Atazanavir: Atazanavir 400mg once daily for 7 days followed by atazanavir 300mg plus ritonavir 100mg for 7 days | 15 |
| CYP3A5 Non-expressors A pre-screening genetic test determines CYP3A5 non-expressor status
Atazanavir: Atazanavir 400mg once daily for 7 days followed by atazanavir 300mg plus ritonavir 100mg for 7 days | 16 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Day 14 | Adverse Event | 1 | 4 |
Baseline characteristics
| Characteristic | CYP3A5 Expressors | CYP3A5 Non-expressors | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 16 Participants | 31 Participants |
| Race/Ethnicity, Customized African American | 7 Participants | 6 Participants | 13 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 4 Participants | 9 Participants | 13 Participants |
| Race/Ethnicity, Customized Hispanic | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 16 |
| other Total, other adverse events | 1 / 15 | 4 / 16 |
| serious Total, serious adverse events | 0 / 15 | 0 / 16 |
Outcome results
Primary
Day 7 Atazanavir Oral Clearance
Measure atazanavir oral clearance in genetically-determined CYP3A5 expressors versus CYP3A5 non-expressors
Time frame: Day 7
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| CYP3A5 Expressors | Day 7 Atazanavir Oral Clearance | .25 L/h/kg |
| CYP3A5 Non-expressors | Day 7 Atazanavir Oral Clearance | .18 L/h/kg |