Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics

NCT00668395 | Completed Results DMC

• 1 other identifier: 1010002585 | 0704-14
• Study Type: interventional
• Target: 73
• Locations: 1 country
• Sites: 2

Brief Summary

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

Conditions

HIV

Keywords

CYP2B6; Efavirenz; Pharmacokinetics; Pharmacogenetics; Drug-Interactions

Outcome Measures

Primary Outcomes (1)

• Effect of CYP2B6 Genotype on Efavirenz Clearance

  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.

  Efavirenz clearance at single dose and multiple dose stratified by CYP2B6 genotypes

Study Arms (3)

CYP2B6*1/*1 genotype

OTHER

Efavirenz clearance in this genotype was compared with the other genotypes

Drug: Efavirenz

CYP2B6*1/*6

OTHER

Efavirenz clearance in this genotype was compared with the other genotypes

Drug: Efavirenz

CYP2B6*6/*6

OTHER

Efavirenz clearance in this genotype was compared with the other genotypes

Drug: Efavirenz

Interventions

Efavirenz DRUG

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).

Also known as: Sustiva

CYP2B6*1/*1 genotype; CYP2B6*1/*6; CYP2B6*6/*6

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Indiana University: lead

Study Sites (2)

Indiana Clinical Research Center (ICRC)

Indianapolis, Indiana, 46202, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Related Publications (9)

• 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. doi: 10.2174/138920006778520633.

  PMID: 17073575 BACKGROUND

• 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. doi: 10.1016/j.pharmthera.2006.10.002. Epub 2006 Oct 24.

  PMID: 17157385 BACKGROUND

• Ekins S, Wrighton SA. The role of CYP2B6 in human xenobiotic metabolism. Drug Metab Rev. 1999 Aug;31(3):719-54. doi: 10.1081/dmr-100101942. No abstract available.

  PMID: 10461547 BACKGROUND

• Lang T, Klein K, Fischer J, Nussler 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. doi: 10.1097/00008571-200107000-00004.

  PMID: 11470993 BACKGROUND

• 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. doi: 10.1124/jpet.104.068973. Epub 2004 Jun 9.

  PMID: 15190123 BACKGROUND

• 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. doi: 10.1097/01213011-200512000-00004.

  PMID: 16272958 BACKGROUND

• Collins KS, Aruldhas BW, Metzger IF, Lu JBL, Heathman MA, Quinney SK, Desta Z. A Population Pharmacokinetic Approach to Understand the Effect of Efavirenz on CYP3A Activity in Healthy Volunteers Using Midazolam as a Probe. CPT Pharmacometrics Syst Pharmacol. 2025 Dec;14(12):2095-2106. doi: 10.1002/psp4.70116. Epub 2025 Sep 24.

  PMID: 40991845 DERIVED

• Robarge JD, Metzger IF, Lu J, Thong N, Skaar TC, Desta Z, Bies RR. Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition. Antimicrob Agents Chemother. 2016 Dec 27;61(1):e01813-16. doi: 10.1128/AAC.01813-16. Print 2017 Jan.

  PMID: 27799204 DERIVED

• Metzger IF, Quigg TC, Epstein N, Aregbe AO, Thong N, Callaghan JT, Flockhart DA, Nguyen AT, Stevens CK, Gupta SK, Desta Z. Substantial effect of efavirenz monotherapy on bilirubin levels in healthy volunteers. Curr Ther Res Clin Exp. 2014 Sep 27;76:64-9. doi: 10.1016/j.curtheres.2014.05.002. eCollection 2014 Dec.

  PMID: 25352936 DERIVED

MeSH Terms

Interventions

efavirenz

Results Point of Contact

• Title: Zeruesenay Desta, PhD
• Organization: Indiana University School of Medicine

zdesta@iu.edu

317-274-2823

Study Officials

• Zeruesenay Desta, PhD

  Indiana University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 27, 2007
• First Posted: April 29, 2008
• Study Start: May 1, 2007
• Primary Completion: April 1, 2010
• Study Completion: April 1, 2010
• Last Updated: September 26, 2014
• Results First Posted: September 26, 2014

Record last verified: 2014-09

Locations

US (2)