Effect of Genetics on Metabolism of Efavirenz
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|ClinicalTrials.gov Identifier: NCT00245986|
Recruitment Status : Completed
First Posted : October 28, 2005
Last Update Posted : July 2, 2017
|First Submitted Date ICMJE||October 27, 2005|
|First Posted Date ICMJE||October 28, 2005|
|Last Update Posted Date||July 2, 2017|
|Study Start Date ICMJE||October 18, 2005|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE||Not Provided|
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT00245986 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Effect of Genetics on Metabolism of Efavirenz|
|Official Title ICMJE||Pharmacogenetics of Efavirenz Metabolism: Association of CYP2B6 Genotype and Prolonged Drug Exposure|
This study will evaluate the effects of genetics on metabolism of the anti-HIV medicine efavirenz (Sustiva) and will see if Efavirenz interacts with bupropion (Zyban or Wellbutrin), a drug commonly used to treat depression and to help people quit smoking. Efavirenz is metabolized by an enzyme called CYP2B6, which is thought to be more active in some people than in others, depending on their genetic makeup. The rate of metabolism of the drug can affect how the body responds it and perhaps the ability of the HIV virus to develop resistance to it.
Healthy volunteers between 18 and 55 years of age who are non-smokers and HIV-infected men and women 18 years of age and older who are taking efavirenz along with two or three nucleoside reverse transcriptase inhibitors may be eligible for this study. Candidates are screened with a medical history and physical examination and blood tests, including tests to determine which genes they have for four different proteins or enzymes (CYP2B6, CYP3A4, CYP3A5, and MDR1) that metabolize drugs.
Participants are assigned to one of three groups for the following procedures:
-HIV-infected individuals: Blood samples are drawn to measure efavirenz levels, as follows: On the last day of taking efavirenz, the subject skips his or her usual evening efavirenz dose the night before sampling. The next morning at clinic, a catheter (flexible plastic tube) is inserted into a vein in the subject's arm for collecting blood samples. After the first sample is drawn, the subject takes a dose of efavirenz. Eight more blood samples are collected at 1, 2, 4, 6, 8, 12, 24 and 48 hours after taking the efavirenz tablet. (The catheter is removed after the 12-hour sample and the subject is discharged home, and then returns to the clinic for the 24- and 48-hour samples, which are collected through a needle inserted into an arm vein.) The subject returns to the clinic four more times for a single blood draw at 7, 14, 21 and 28 days after stopping efavirenz.
HIV-infected patients whose HIV viral load reaches 1,000 copies/L or more within 12 months after completing the study are asked to return to the clinic for a blood draw to check the genotype of the virus for drug resistance.
Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with a long half-life, allowing for once-daily dosing. Although it is generally well-tolerated and widely used, a major disadvantage of EFV is its relatively low barrier to resistance. The single K103N mutation confers high-level resistance to EFV, as well as to all other NNRTI's. Acquisition of HIV-1 resistance is likely to result from repeated exposure of the virus to subtherapeutic drug concentrations.
When terminating EFV therapy it is recommended that EFV be stopped 1-2 weeks earlier than concomitant antiretrovirals (ARVs) to account for its long washout period. Alternatively, substituting EFV with a protease inhibitor for 1 to 4 weeks has also been recommended. Both strategies attempt to avoid prolonged EFV exposure following discontinuation of concomitant ARVs, thereby lowering the risk of acquiring new resistance mutations. Though widely utilized, neither method has been validated by pharmacokinetic or clinical studies. Genetic differences in CYP2B6 contribute greatly to observed variability in EFV clearance; hence, genetic differences may contribute to significantly different responses to methods of therapy discontinuation. Multiple polymorphisms in CYP2B6 have been identified. Substitutions at positions 516, 785, and 1459 are the most common variants, and appear to be associated with alterations in CYP2B6 activity.
We propose a 2-part study. Part I is to be conducted in HIV-negative volunteers, and consists of: (1) determination of EFV pharmacokinetic (PK) values (following 13-15 days of EFV 600 mg/day) for comparison between CYP2B6 genotypes (including wild-type and allelic variants at positions 516, 785 and 1459), (2) measurement of single EFV plasma concentrations 7, 14, 21, and 28 days after the drug is stopped to assess for differences in EFV exposure between CYP2B6 genotypes, and (3) comparison of bupropion PK values following administration of a single bupropion dose (a) prior to EFV administration and (b) after 13-15 days of EFV, to evaluate whether EFV modulates CYP2B6 metabolism using bupropion as a probe for CYP2B6 function.
Part II is to be conduced in HIV-positive patients who are planning to discontinue (d/c) their EFV therapy, and includes: (1) determination of EFV PK values prior to d/c of therapy for comparison between different CYP2B6 genotypes, (2) measurement of single EFV plasma concentrations 7, 14, 21 and 28 days post-EFV to assess for differences in exposure across CYP2B6 genotypes, and (3) genotypic evaluation of HIV-1 drug resistance performed in any patient with an HIV RNA = 1,000 copies/mL, prior to and after EFV discontinuation (up to 12 months after stopping EFV), as a preliminary study to evaluate the incidence of EFV resistance mutations based on CYP2B6 genotype.
Data from this study will help to describe the relationship between CYP2B6 genetic polymorphisms and the PK variability of EFV, specifically addressing the effect on prolonged EFV exposure following discontinuation of therapy. In addition, this study will determine whether EFV modulates CYP2B6 activity as assessed by bupropion phenotyping. Lastly, it will attempt to provide preliminary information about whether genetic variability in CYP2B6 is related to the incidence of NNRTI-resistance after stopping or changing EFV therapy.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 4|
|Study Design ICMJE||Primary Purpose: Treatment|
|Intervention ICMJE||Procedure: Blood draw|
|Study Arms||Not Provided|
|Publications *||Haas DW, Fessel WJ, Delapenha RA, Kessler H, Seekins D, Kaplan M, Ruiz NM, Ploughman LM, Labriola DF, Manion DJ. Therapy with efavirenz plus indinavir in patients with extensive prior nucleoside reverse-transcriptase inhibitor experience: a randomized, double-blind, placebo-controlled trial. J Infect Dis. 2001 Feb 1;183(3):392-400. Epub 2000 Dec 29.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Original Enrollment ICMJE||Same as current|
|Study Completion Date||May 20, 2008|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
5.) Ability to abstain from eating grapefruit or drinking grapefruit juice during EFV administration and EFV PK sampling periods.
6.) Negative serum pregnancy test for females of child-bearing potential (within 1 day before starting EFV).
7.) Females of child-bearing potential who are able and willing to either practice abstinence or use two non-hormonal forms of birth control (such as condoms, diaphragms, IUDs, etc.) while taking EFV and up to the 28th day after their last EFV dose.
8.) Non-smokers for at least 1 month prior to study participation.
1.) Concomitant therapy with a PI or any NNRTI other than EFV for 30 days prior to study participation.
2,) Concomitant therapy with any prescription, over-the-counter, herbal, or holistic medications that are known to interact with EFV or modulate CYP2B6 activity for 14 days prior to study participation.
3.) Inability to obtain venous access for blood sample collection.
4.) The presence of any of the following: Any active opportunistic infection (including, but not limited to tuberculosis, Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci, Cryptococcus neoformans, and esophageal candidiasis), renal disease (chronic or acute renal failure or insufficiency), hepatic impairment, pancreatitis, or any other condition that may interfere with the interpretation of the study results or not be in the best interest of the subject in the opinion of the investigators.
5.) A previously documented history of persistent diarrhea or malabsorption that would interfere with the subject's ability to absorb drugs.
6.) Drug or alcohol abuse that may impair safety or adherence or interfere with the study results.
7.) Non-adherence to efavirenz therapy (regularly misses greater than 1 dose/week)
8.) Positive pregnancy test or breastfeeding female.
9.) Severe or potentially life-threatening adverse event/toxicitiy from efavirenz, such that administration of an additional dose of efavirenz would be unsafe and is deemed unwarranted by the study personnel or the patient's primary physician.
|Ages||18 Years to 55 Years (Adult)|
|Accepts Healthy Volunteers||Yes|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00245986|
|Other Study ID Numbers ICMJE||060006
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||National Institutes of Health Clinical Center (CC)|
|Collaborators ICMJE||Not Provided|
|Investigators ICMJE||Not Provided|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||May 20, 2008|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP