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Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics

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ClinicalTrials.gov Identifier: NCT00668395
Recruitment Status : Completed
First Posted : April 29, 2008
Results First Posted : September 26, 2014
Last Update Posted : September 26, 2014
Sponsor:
Information provided by (Responsible Party):
Indiana University

Tracking Information
First Submitted Date  ICMJE November 27, 2007
First Posted Date  ICMJE April 29, 2008
Results First Submitted Date  ICMJE April 10, 2013
Results First Posted Date  ICMJE September 26, 2014
Last Update Posted Date September 26, 2014
Study Start Date  ICMJE May 2007
Actual Primary Completion Date April 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 18, 2014)
Effect of CYP2B6 Genotype on Efavirenz Clearance [ Time Frame: Efavirenz clearance at single dose and multiple dose stratified by CYP2B6 genotypes ]
Efavirenz clearance is a measure of rate of elimination of the drug from the body. We used this measure to evaluate differences in rate of elimination of efavirenz at a single dose and after multiple dosing within three CYP2B6 genotypes (CYP2B6*1/*1, *1/*6 and CYP2B6*6/*6). Efavirenz clearance was measured in normal metabolizer of CYP2B6 (CYP2B6*1/*1 genotype), intermediate metabolizer (CYP2B6*1/*6) and slow metabolizer (CYP2B6*6/*6) at a single 600 mg oral dose of efavirenz and then after multiple dosing (autoinduction), i.e., the administration of efavirenz (600 mg/day) for 17 days. Single and multiple dose efavirenz clearance was measured and compared to determine the extent of autoinduction within this genotype group.
Original Primary Outcome Measures  ICMJE
 (submitted: April 28, 2008)
Determine the pharmacokinetics of single and multiple doses of efavirenz in healthy volunteers genotyped for the CYP2B6*6 allele. [ Time Frame: 4 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: April 28, 2008)
Develop and test an autoinduction pharmacokinetic model and assess the effect of the CYP2B6*6 allele genotypes. [ Time Frame: 4 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics
Official Title  ICMJE Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics, Autoinduction and Drug Interactions in Healthy Volunteers.
Brief Summary
  1. To see how the liver breaks down efavirenz by an enzyme called CYP2B6. It is suggested that when Efavirenz is taken repeatedly it may increase the amount of CYP2B6 in your liver and thus speed up your liver's ability to get rid of efavirenz from your body. This may render efavirenz and other medications ineffective.
  2. To see how efavirenz interact with other drugs taken at the same time with it.
  3. To see if genetic differences can change the way how the liver breaks down efavirenz and its interactions with other co-administered drugs.
Detailed Description The human hepatic cytochrome P450 2B6 (CYP2B6) is a key enzyme in the metabolism of a growing list of clinically important drugs, environmental chemicals (e.g. toxicants and carcinogens) and endogenous substances. The expression and activity of this enzyme varies widely among individuals, probably due to genetic polymorphisms in the CYP2B6 gene and drug interactions. This variability, in turn, likely contributes to variable response to those drugs primarily metabolized by CYP2B6. In deed, several drugs that are substrates of CYP2B6 exhibit large pharmacokinetic differences among individuals and their use is associated with unpredictable drug interactions. Therefore, identifying mechanisms and factors that might influence CYP2B6 activity is important to the safe and effective use of its substrates. An important characteristic of several clinically important CYP2B6 substrate drugs that include efavirenz, nevirapine, cyclophosphamide, artemisinin and ifosfamide is their ability to enhance their own clearance upon repeated dosing, a process known as autoinduction of metabolism. Drugs that autoinduce metabolism also exhibit multiple interactions with drug metabolizing enzymes other than CYP2B6 (e.g. CYP3A, CYP2C9 and CYP2C19), and drug transporters (e.g. p-glycoprotein). As most of these medications are used in combination with other drugs, their potential to alter the pharmacokinetics of co-administered drugs is very high. We hypothesize that CYP2B6 genetic variants that influence constitutive CYP2B6 expression and activity contribute to interindividual variability in steady-state exposure of the autoinducer drugs and in the drug interactions that ensue. We will determine the impact of CYP2B6 genetic variants, typically the CYP2B6*6 allele, on the time-course and extent of autoinduction of metabolism and the consequences of differential autoinduction on drug interactions, using efavirenz (a known CYP2B6 substrate and an autoinducer) as a model drug. Thus, single (600 mg oral dose) and steady-state (600 mg/day) pharmacokinetics of efavirenz will be assessed in healthy subjects genotyped for the CYP2B6*6 allele. Trough concentrations of efavirenz and its metabolites will be collected during the course of efavirenz treatment. Efavirenz exposure will be compared between the genotypes after autoinduction. An autoinduction pharmacokinetic model will be developed to characterize the dynamics and time courses of autoinduction in the different genotypes. The potential impact of differences in efavirenz exposure on drug interactions will be determined by measuring the in vivo activity of selected CYP enzymes, using isoform specific substrate probes [omeprazole (CYP2C19), tolbutamide (CYP2C9), caffeine (CYP1A2) and midazolam (CYP3A)] at single and after multiple (steady-state) dosing with efavirenz.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE HIV
Intervention  ICMJE Drug: Efavirenz
The metabolism and pharmacokinetics of efavirenz were assessed at a single 600 mg oral dose of efavirenz and after subjects took multiple doses of efavirenz (600 mg/day orally for 17 days).
Other Name: Sustiva
Study Arms  ICMJE
  • CYP2B6*1/*1 genotype
    Efavirenz clearance in this genotype was compared with the other genotypes
    Intervention: Drug: Efavirenz
  • CYP2B6*1/*6
    Efavirenz clearance in this genotype was compared with the other genotypes
    Intervention: Drug: Efavirenz
  • CYP2B6*6/*6
    Efavirenz clearance in this genotype was compared with the other genotypes
    Intervention: Drug: Efavirenz
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 18, 2014)
73
Original Estimated Enrollment  ICMJE
 (submitted: April 28, 2008)
60
Actual Study Completion Date  ICMJE April 2010
Actual Primary Completion Date April 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male and female subjects between 18 and 49 years old.
  2. HIV negative. All potential subjects will be HIV tested at screening visit.
  3. Healthy individuals without any significant medical condition.
  4. Adherence to the study dietary restrictions.
  5. Nonsmoker or individuals willing to refrain from smoking or use of tobacco or marijuana for at lest one month prior to and until the completion of the study. The entire study lasts for 30 days.
  6. Ability to commit the time requested for this study.

Exclusion Criteria:

  1. History or current HIV infection.
  2. Life style that places you at a higher risk for contracting HIV (e.g. drug abuse, excessive alcohol drinking, and having multiple sexual partners).
  3. Does not consent to HIV testing.
  4. Underweight (weigh less than 52 kg or 114 lb) or overweight (body mass index (BMI) greater than 32).
  5. History or current alcohol or drug abuse (more than 3 alcoholic drinks per day on a regular basis).
  6. History of intolerance or allergic reaction (e.g. rash) to efavirenz, midazolam, tolbutamide, caffeine, or omeprazole.
  7. History or current significant health conditions such as heart, liver, or kidney.
  8. History or current psychiatric illness such as depression, anxiety, or nervousness.
  9. History or current gastrointestinal disorders such as persistent diarrhea or malabsorption that would interfere with the absorption of orally administered drugs.
  10. Individuals having a serious infection within the last month.
  11. Donation of blood within the past two months.
  12. Blood hemoglobin less than 12.5 mg/dl.
  13. Individuals who are regularly taking prescriptions, over-the-counter, herbal or dietary supplements, alternative medications, or hormonal agents (i.e. oral contraceptives, intera-uterine device with hormones).
  14. Females with a positive pregnancy test.
  15. Breastfeeding.
  16. Females of child-bearing potential who are unable or unwilling to either practice abstinence or use two non-hormonal forms of birth control (e.g. condom, contraceptive foams) up until the study completion, which will take a total of 30 days.
  17. Participation in a research study or use of an investigational drug in the last two months.
  18. An employee or student under supervision of any of the investigators of this study.
  19. Individuals who cannot state a good understanding of this study including risks and requirements; are unable to follow the rules of this study.
  20. Individuals with a gene type (DNA) that does not match one of the available genetic slot categories.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 49 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00668395
Other Study ID Numbers  ICMJE 1010002585 | 0704-14
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Indiana University
Study Sponsor  ICMJE Indiana University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Zeruesenay Desta, PhD Indiana University
PRS Account Indiana University
Verification Date September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP