Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics
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First Received Date ICMJE | November 27, 2007 | ||||
Last Updated Date | October 7, 2011 | ||||
Start Date ICMJE | May 2007 | ||||
Primary Completion Date | April 2010 (final data collection date for primary outcome measure) | ||||
Current Primary Outcome Measures ICMJE |
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 ] | ||||
Original Primary Outcome Measures ICMJE | Same as current | ||||
Change History | Complete list of historical versions of study NCT00668395 on ClinicalTrials.gov Archive Site | ||||
Current Secondary Outcome Measures ICMJE |
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 ] | ||||
Original Secondary Outcome Measures ICMJE | Same as current | ||||
Current Other Outcome Measures ICMJE | |||||
Original Other Outcome Measures ICMJE | |||||
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 |
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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. |
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Study Type ICMJE | Interventional | ||||
Study Phase | |||||
Study Design ICMJE | Allocation: Non-Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Screening |
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Condition ICMJE |
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Intervention ICMJE | 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. |
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Study Arm (s) |
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Publications * |
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||
Recruitment Status ICMJE | Completed | ||||
Estimated Enrollment ICMJE | 60 | ||||
Completion Date | April 2010 | ||||
Primary Completion Date | April 2010 (final data collection date for primary outcome measure) | ||||
Eligibility Criteria ICMJE | Inclusion Criteria:
Exclusion Criteria:
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Gender | Both | ||||
Ages | 18 Years to 49 Years | ||||
Accepts Healthy Volunteers | Yes | ||||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||
Location Countries ICMJE | United States | ||||
Administrative Information | |||||
NCT Number ICMJE | NCT00668395 | ||||
Other Study ID Numbers ICMJE | 0704-14, 1436A | ||||
Has Data Monitoring Committee | Yes | ||||
Responsible Party | Desta Zeruesenay, PhD, Indiana University | ||||
Study Sponsor ICMJE | Indiana University | ||||
Collaborators ICMJE | National Institutes of Health (NIH) | ||||
Investigators ICMJE |
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Information Provided By | Indiana University | ||||
Verification Date | October 2011 | ||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |