Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics - Full Text View

Sponsor:	Indiana University
Collaborator:	National Institutes of Health (NIH)
Information provided by:	Indiana University
ClinicalTrials.gov Identifier:	NCT00668395

Purpose

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.
To see how efavirenz interact with other drugs taken at the same time with it.
To see if genetic differences can change the way how the liver breaks down efavirenz and its interactions with other co-administered drugs.

Condition	Intervention
Metabolism Pharmacokinetics	Drug: Efavirenz

Study Type:	Interventional
Study Design:	Screening, Open Label, Single Group Assignment, Pharmacokinetics/Dynamics Study
Official Title:	Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics, Autoinduction and Drug Interactions in Healthy Volunteers.

Resource links provided by NLM:

Genetics Home Reference related topics: Help Me Understand Genetics

Drug Information available for: Efavirenz

U.S. FDA Resources

Further study details as provided by Indiana University:

Primary Outcome Measures:

Determine the pharmacokinetics of single and multiple doses of efavirenz in healthy volunteers genotyped for the CYP2B6*6 allele. [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Develop and test an autoinduction pharmacokinetic model and assess the effect of the CYP2B6*6 allele genotypes. [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment:	60
Study Start Date:	May 2007
Estimated Study Completion Date:	June 2012
Estimated Primary Completion Date:	June 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
CYP2B61/1: Active Comparator n=20	Drug: Efavirenz the subjects will receive efavirenz (600 mg single dose) orally with approximately 240 ml of water. One hour later, an oral cocktail of 250 mg of tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 150 mg of caffeine (CYP1A2) and 1 mg of midazolam syrup (CYP3A) will be administered with water.
CYP2B61/6: Active Comparator n=20	Drug: Efavirenz the subjects will receive efavirenz (600 mg single dose) orally with approximately 240 ml of water. One hour later, an oral cocktail of 250 mg of tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 150 mg of caffeine (CYP1A2) and 1 mg of midazolam syrup (CYP3A) will be administered with water.
CYP2B66/6: Active Comparator n=20	Drug: Efavirenz the subjects will receive efavirenz (600 mg single dose) orally with approximately 240 ml of water. One hour later, an oral cocktail of 250 mg of tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 150 mg of caffeine (CYP1A2) and 1 mg of midazolam syrup (CYP3A) will be administered with water.

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.

Eligibility

Ages Eligible for Study:	18 Years to 49 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Male and female subjects between 18 and 49 years old.
HIV negative. All potential subjects will be HIV tested at screening visit.
Healthy individuals without any significant medical condition.
Adherence to the study dietary restrictions.
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.
Ability to commit the time requested for this study.

Exclusion Criteria:

History or current HIV infection.
Life style that places you at a higher risk for contracting HIV (e.g. drug abuse, excessive alcohol drinking, and having multiple sexual partners).
Does not consent to HIV testing.
Underweight (weigh less than 52 kg or 114 lb) or overweight (body mass index (BMI) greater than 32).
History or current alcohol or drug abuse (more than 3 alcoholic drinks per day on a regular basis).
History of intolerance or allergic reaction (e.g. rash) to efavirenz, midazolam, tolbutamide, caffeine, or omeprazole.
History or current significant health conditions such as heart, liver, or kidney.
History or current psychiatric illness such as depression, anxiety, or nervousness.
History or current gastrointestinal disorders such as persistent diarrhea or malabsorption that would interfere with the absorption of orally administered drugs.
Individuals having a serious infection within the last month.
Donation of blood within the past two months.
Blood hemoglobin less than 12.5 mg/dl.
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).
Females with a positive pregnancy test.
Breastfeeding.
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.
Participation in a research study or use of an investigational drug in the last two months.
An employee or student under supervision of any of the investigators of this study.
Individuals who cannot state a good understanding of this study including risks and requirements; are unable to follow the rules of this study.
Individuals with a gene type (DNA) that does not match one of the available genetic slot categories.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00668395

Contacts

Contact: Nancy Thong, RN,CCRP	317-630-8088	nthong@ipui.edu
Contact: Zeruesenay Desta, PhD	317-630-8795	zdesta@iupui.edu

Locations

United States, Indiana
Indiana University	Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Nancy Thong, RN, CCRP 317-630-8088 nthong@iupui.edu
Principal Investigator: Zeruesenay Desta, PhD

Sponsors and Collaborators

Indiana University

National Institutes of Health (NIH)

Investigators

Principal Investigator:

Zeruesenay Desta, PhD

Indiana University

More Information

Additional Information:

Cytochrome P450 Drug Interaction Site This link exits the ClinicalTrials.gov site

Publications:

Turpeinen M, Raunio H, Pelkonen O. The functional role of CYP2B6 in human drug metabolism: substrates and inhibitors in vitro, in vivo and in silico. Curr Drug Metab. 2006 Oct;7(7):705-14. Review.

Hodgson E, Rose RL. The importance of cytochrome P450 2B6 in the human metabolism of environmental chemicals. Pharmacol Ther. 2007 Feb;113(2):420-8. Epub 2006 Oct 24. Review.

Ekins S, Wrighton SA. The role of CYP2B6 in human xenobiotic metabolism. Drug Metab Rev. 1999 Aug;31(3):719-54. Review. No abstract available.

Lang T, Klein K, Fischer J, Nüssler AK, Neuhaus P, Hofmann U, Eichelbaum M, Schwab M, Zanger UM. Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics. 2001 Jul;11(5):399-415. Erratum in: Pharmacogenetics 2001 Oct;11(7):643.

Lang T, Klein K, Richter T, Zibat A, Kerb R, Eichelbaum M, Schwab M, Zanger UM. Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles. J Pharmacol Exp Ther. 2004 Oct;311(1):34-43. Epub 2004 Jun 9.

Klein K, Lang T, Saussele T, Barbosa-Sicard E, Schunck WH, Eichelbaum M, Schwab M, Zanger UM. Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz. Pharmacogenet Genomics. 2005 Dec;15(12):861-73.

Responsible Party:	Indiana University ( Desta Zeruesenay, PhD )
Study ID Numbers:	0704-14, 1436A
Study First Received:	November 27, 2007
Last Updated:	April 28, 2008
ClinicalTrials.gov Identifier:	NCT00668395 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by Indiana University:

CYP2B6
Efavirenz
Pharmacokinetics
Pharmacogenetics
Drug-Interactions

Additional relevant MeSH terms:

Anti-Infective Agents
Efavirenz
Anti-HIV Agents
Anti-Retroviral Agents
Molecular Mechanisms of Pharmacological Action
Therapeutic Uses

Enzyme Inhibitors
Antiviral Agents
Pharmacologic Actions
Nucleic Acid Synthesis Inhibitors
Reverse Transcriptase Inhibitors

ClinicalTrials.gov processed this record on February 08, 2010