Genetics and HIV-1 Protease Inhibitors

Genetic-determinants of Protease Inhibitor Pharmacology

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.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Atazanavir

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver and Health Sciences Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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: Norvir; Reyataz
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: Norvir; Reyataz

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Peter L. Anderson, PharmD, University of Colorado Denver and Health Sciences Center

Publications and helpful links

General Publications

• Anderson PL, Aquilante CL, Gardner EM, Predhomme J, McDaneld P, Bushman LR, Zheng JH, Ray M, MaWhinney S. Atazanavir pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors. J Antimicrob Chemother. 2009 Nov;64(5):1071-9. doi: 10.1093/jac/dkp317. Epub 2009 Aug 26.
• Wempe MF, Anderson PL. Atazanavir metabolism according to CYP3A5 status: an in vitro-in vivo assessment. Drug Metab Dispos. 2011 Mar;39(3):522-7. doi: 10.1124/dmd.110.036178. Epub 2010 Dec 9.
• Kile DA, MaWhinney S, Aquilante CL, Rower JE, Castillo-Mancilla JR, Anderson PL. A population pharmacokinetic-pharmacogenetic analysis of atazanavir. AIDS Res Hum Retroviruses. 2012 Oct;28(10):1227-34. doi: 10.1089/aid.2011.0378. Epub 2012 Apr 20.

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: June 28, 2011
• First Submitted That Met QC Criteria: July 1, 2011
• First Posted (Estimate): July 6, 2011

Study Record Updates

• Last Update Posted (Actual): November 19, 2019
• Last Update Submitted That Met QC Criteria: October 31, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: HIV; Pharmacokinetics; Pharmacogenomics; Clinical Pharmacology
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Atazanavir Sulfate
• Other Study ID Numbers: 06-0428; R03AI068438 (U.S. NIH Grant/Contract); BMSV-338 (Other Grant/Funding Number: Bristol-Myers Squibb)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No plan to share