Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics

Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics, Autoinduction and Drug Interactions in Healthy Volunteers.

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.

Study Overview

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

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: Interventional
• Enrollment (Actual): 73
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
    • Indianapolis, Indiana, United States, 46202
      • Indiana Clinical Research Center (ICRC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: CYP2B6*1/*1 genotype; Efavirenz clearance in this genotype was compared with the other genotypes	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 Names: Sustiva
OTHER: CYP2B6*1/*6; Efavirenz clearance in this genotype was compared with the other genotypes	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 Names: Sustiva
OTHER: CYP2B6*6/*6; Efavirenz clearance in this genotype was compared with the other genotypes	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 Names: Sustiva

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Indiana University

Publications and helpful links

General 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. doi: 10.2174/138920006778520633.
• 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.
• 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.
• 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. 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. doi: 10.1124/jpet.104.068973. 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. doi: 10.1097/01213011-200512000-00004.
• 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.
• 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.

Helpful Links

• Cytochrome P450 Drug Interaction Site

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (ACTUAL): April 1, 2010
• Study Completion (ACTUAL): April 1, 2010

Study Registration Dates

• First Submitted: November 27, 2007
• First Submitted That Met QC Criteria: April 28, 2008
• First Posted (ESTIMATE): April 29, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): September 26, 2014
• Last Update Submitted That Met QC Criteria: September 18, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Efavirenz; Pharmacogenetics; CYP2B6; Drug-Interactions
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Efavirenz
• Other Study ID Numbers: 1010002585 | 0704-14