Comparative Effects of Azithromycin, Telithromycin and Levofloxacin on Drug Metabolizing Enzymes
|First Submitted Date ICMJE||September 9, 2005|
|First Posted Date ICMJE||September 14, 2005|
|Last Update Posted Date||December 9, 2005|
|Start Date ICMJE||November 2004|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||No Changes Posted|
|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||Comparative Effects of Azithromycin, Telithromycin and Levofloxacin on Drug Metabolizing Enzymes|
|Official Title ICMJE||Comparison of the Effect of Azithromycin, Telithromycin and Levofloxacin on Drug Metabolizing Enzymes Using the Validated Cooperstown 5+1 Cocktail|
|Brief Summary||Studies have previously shown that a broad drug interaction screening can be performed using enzyme specific probes such as oral caffeine for CYP1A2, N-acetyltrasferase-2 (NAT-2), and xanthine oxidase (XO), warfarin plus vitamin K for CYP2C9, omeprazole for CYP 2C19, dextromethorphan for CYP2D6, and midazolam for CYP3A4/5. This combination of probes has been validated in the Cooperstown 5+1 Cocktail (5+1).1 The use of the 5+1 cocktail provides information on the drug metabolizing enzymes that metabolize 90% of hepatically eliminated drugs for a fraction of the costs of the individual studies. Using a cocktail of biomarkers reduces the overall cost of drug interaction screening. The purpose of this study is to evaluate the effects of three Food and Drug Administration (FDA) approved oral antibiotics (azithromycin, telithromycin, and levofloxacin) on metabolism of other medications when taken together. This will be determined by the measuring the activity of drug metabolizing enzymes following administration of certain drug probes (caffeine, dextromethorphan, omeprazole, midazolam, and warfarin with vitamin K). A total of 16 subjects will complete four phases of the study: 1) Cooperstown 5+1 alone, 2) Azithromycin plus Cooperstown 5+1, 3) Telithromycin plus Cooperstown 5+1, and 4) Levofloxacin plus Cooperstown 5+1.|
We have previously shown that a broad drug interaction screening can be performed using enzyme specific probes such as oral caffeine for CYP1A2, N-acetyltrasferase-2 (NAT-2), and xanthine oxidase (XO), warfarin plus vitamin K for CYP2C9, omeprazole for CYP 2C19, dextromethorphan for CYP2D6, and midazolam for CYP3A4/5. This combination of probes has been validated in the Cooperstown 5+1 Cocktail (5+1).1 The use of the 5+1 cocktail provides information on the drug metabolizing enzymes that metabolize 90% of hepatically eliminated drugs for a fraction of the costs of the individual studies. Using a cocktail of biomarkers reduces the overall cost of drug interaction screening. The FDA has indicated that the use of probe drugs can be done in place of specific drug interaction studies.2 This streamlines the detection of drug interactions and reduces costs. However, it is important to control for genetic polymorphism in drug interaction trials so that genetic makeup does not affect the outcome.
Experimental Design and Methods 3) Describe in detail the experimental design and methodology. What information will be collected and how will it be collected? Provide a description of the subject’s participation from start to finish.
Prior to any procedure of the study each subject will provide written informed consent. All the subjects will be genotyped for CYP2D6, CYP2C9, and CYP2C19 after obtaining informed consent for pharmacogenomics. This is to distinguish poor metabolizers from extensive metabolizers.
Prestudy screening will be conducted within 4 weeks of the first study phase. Subjects will undergo a complete medical history, social history (including medication, alcohol, and tobacco use), physical examination, standard 12-lead electrocardiogram (ECG), and laboratory screening to assure that inclusion and exclusion criteria are met. The laboratory screening data to be obtained are: complete blood count, prothrombin time (PT), international normalized ratio (INR), macroscopic and microscopic urinalysis, electrolytes, blood urea nitrogen (BUN), serum creatinine, aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, and serum albumin. Women of childbearing potential (defined as premenopausal with no history of hysterectomy or tubal ligation) will undergo a serum pregnancy test during the screening visit and a urine pregnancy test prior to each phase of the study. Following enrollment, subjects will participate in each of the 4 study phases in a random order.
Study Design and Procedures This will be a randomized, crossover, open-label study. Prestudy screening will be conducted within 4 weeks of the first study phase. Screening visits will involve obtaining informed consent, medical history, social history, physical examination, ECG, and laboratory tests. Following enrollment, subjects will be randomized (and then crossed over) to 4 phases as described in Table 1.
Table 1. Study Design Study Drugs and Procedure Phase 1 (control) Cooperstown 5+1 Cocktail alone. The Cooperstown 5+1 Cocktail consists of the following components:
4) If the research is in part a treatment protocol, identify which parts are routine and which parts are being done solely for research.
This study is for research purposes.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 4|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
|Study Arms||Not Provided|
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Estimated Completion Date||June 2005|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
|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||Not Provided|
|Removed Location Countries|
|NCT Number ICMJE||NCT00164112|
|Other Study ID Numbers ICMJE||CAPSS-273|
|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||Bassett Healthcare|
|Collaborators ICMJE||PriCara, Unit of Ortho-McNeil, Inc.|
|PRS Account||Bassett Healthcare|
|Verification Date||March 2005|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP