Genetics and HIV-1 Protease Inhibitors

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01388543
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 31
• Location: 1
• Arms: 2
• Duration (Months): 21
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HIV	Drug: Atazanavir	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Genetic-determinants of Protease Inhibitor Pharmacology
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Jun 1, 2008

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Day 7 Atazanavir Oral Clearance [Day 7]

   Measure atazanavir oral clearance in genetically-determined CYP3A5 expressors versus CYP3A5 non-expressors

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Denver and Health Sciences Center	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Peter L. Anderson, PharmD, University of Colorado Denver and Health Sciences Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01388543
• Other Study ID Numbers: 06-0428; R03AI068438; BMSV-338
• First Posted: Jul 6, 2011
• Last Update Posted: Nov 19, 2019
• Last Verified: Oct 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Colorado, Denver: Pharmacokinetics; Clinical Pharmacology; Pharmacogenomics; HIV
• Additional relevant MeSH terms: Atazanavir Sulfate

Study Results

Participant Flow

Arm/Group Title	CYP3A5 Expressors	CYP3A5 Non-expressors
Arm/Group Description	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	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
Period Title: Day 7, Primary End Point
STARTED	15	16
COMPLETED	15	16
NOT COMPLETED	0	0
Period Title: Day 7, Primary End Point
STARTED	15	16
COMPLETED	14	12
NOT COMPLETED	1	4

Baseline Characteristics

Arm/Group Title	CYP3A5 Expressors	CYP3A5 Non-expressors	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	15	16	31
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	15 100%	16 100%	31 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	7 46.7%	9 56.3%	16 51.6%
Male	8 53.3%	7 43.8%	15 48.4%
Race/Ethnicity, Customized (Count of Participants)
African American	7 46.7%	6 37.5%	13 41.9%
Hispanic	3 20%	1 6.3%	4 12.9%
Asian	1 6.7%	0 0%	1 3.2%
Caucasian	4 26.7%	9 56.3%	13 41.9%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CYP3A5 Expressors	CYP3A5 Non-expressors
Arm/Group Description	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	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
Measure Participants	15	16
Geometric Mean (95% Confidence Interval) [L/h/kg]	.25	.18

Adverse Events

Time Frame	Time of consenting to study exit (Day 14 or earlier)
Adverse Event Reporting Description	AEs were graded per the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, V1.0 Aug 2009 (US Dept HHS, NIH, NIAID) Available from: http://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf
Arm/Group Title	CYP3A5 Expressor		CYP3A5 Non-expressors
Arm/Group Description	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		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
All Cause Mortality
	CYP3A5 Expressor		CYP3A5 Non-expressors
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/16 (0%)
Serious Adverse Events
	CYP3A5 Expressor		CYP3A5 Non-expressors
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	CYP3A5 Expressor		CYP3A5 Non-expressors
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)		4/16 (25%)
Endocrine disorders
Abnormal Lab- Amylase	0/15 (0%)		1/16 (6.3%)
General disorders
Unspecified viral syndrome-not study related	0/15 (0%)		1/16 (6.3%)
Hepatobiliary disorders
Abnormal Lab- albumin	0/15 (0%)		1/16 (6.3%)
Abnormal Lab- Aspartate transaminase (AST)	0/15 (0%)		1/16 (6.3%)
Skin and subcutaneous tissue disorders
Rash	1/15 (6.7%)		0/16 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.