Clinical trial NCT01388543: Genetics and HIV-1 Protease Inhibitors
Official title: Genetic-determinants of Protease Inhibitor Pharmacology
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV
Keywords: Pharmacokinetics
Clinical Pharmacology
Pharmacogenomics
HIV
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2011-07-06
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Day 7 Atazanavir Oral Clearance
timeFrame: Day 7
Secondary outcomes:
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Denver and Health Sciences Center
state: Colorado
Study officials:
affiliation: University of Colorado Denver and Health Sciences Center
name: Peter L. Anderson, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.