Ignite Creation Date:
2024-05-05 @ 11:54 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00164112
Status:
COMPLETED
Last Update Posted:
2005-09-14
First Post:
2005-09-09
Brief Title:
Comparative Effects of Azithromycin Telithromycin and Levofloxacin on Drug Metabolizing Enzymes
Sponsor:
Bassett Healthcare
Organization:
Bassett Healthcare
Study Overview
Official Title:
Comparison of the Effect of Azithromycin Telithromycin and Levofloxacin on Drug Metabolizing Enzymes Using the Validated Cooperstown 51 Cocktail
Status:
COMPLETED
Status Verified Date:
2005-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 CYP3A45 This combination of probes has been validated in the Cooperstown 51 Cocktail 511 The use of the 51 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 51 alone 2 Azithromycin plus Cooperstown 51 3 Telithromycin plus Cooperstown 51 and 4 Levofloxacin plus Cooperstown 51
Detailed Description:
Specific Aims
1 What is the purpose of this study What question is it designed to answer
To compare the effect of azithromycin telithromycin and levofloxacin on activity of 7 hepatic drug metabolizing enzymes using the Cooperstown 51 Cocktail
Background
2 Why is this study important
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 CYP3A45 This combination of probes has been validated in the Cooperstown 51 Cocktail 511 The use of the 51 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 studies2 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 subjects 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 51 Cocktail alone The Cooperstown 51 Cocktail consists of the following components
1 Caffeine 2 mgkg orally rounded to nearest 50 mg with collection of a 12-hour urine
2 Warfarin 10 mg 10 mg vitamin K orally with collection of plasma over 96 hours Plasma collection times are at 0 3 6 12 24 36 48 72 and 96 hours after dosing The INR will be checked at 48 hours If the INR is 17 5 mg of vitamin K will be administered by mouth daily until the INR is 12
3 Omeprazole 40 mg orally with collection of a plasma sample 2 hours after dosing
4 Dextromethorphan 30 mg orally with collection of a 12-hour urine
5 Midazolam 0075 mgkg orally with collection of 8 plasma samples over 6 hours only for Phase 1 to determine CYP3A activity MDZ CLF mLmin Samples will be drawn immediately after midazolam administration 0 minute then at 5 minute 05 1 2 4 5 and 6 hours Breathing heart rate and oxygen saturation will be monitored via pulse oximetry for the first 90 minutes after midazolam dose
Phase 2 Azithromycin 500 mg qAM for 3 days on an empty stomach On day 4 the Cooperstown 51 Cocktail will be administered with a fourth dose of azithromycin given 2 hours after 51 administration
Phase 3 Telithromycin 800 mg qAM for 3 days on an empty stomach On day 4 the Cooperstown 51 Cocktail will be administered with a fourth dose of telithromycin given 2 hours after 51 administration
Phase 4 Levofloxacin 750 mg qAM for 3 days on an empty stomach On day 4 the Cooperstown 51 Cocktail will be administered with a fourth dose of levofloxacin given 2 hours after 51 administration
During the azithromycin telithromycin and levofloxacin phases plasma samples for midazolam will be collected at 025 075 1 15 2 4 6 8 10 12 and 24 hours to allow for adequate sampling with drugs that potentially inhibit CYP3A The 51 cocktail will be administered on day 4 after a minimum of 8-hour fasting
Subjects will not be allowed to eat until 2 hours after administration of study drugs 51 cocktail or antibiotic
Washout periods One week after each phase except for the azithromycin phase is required to ensure the drug is completely eliminated from the body Three weeks after the azithromycin phase is required since azithromycin has a longer half-life
Sample Collection and Analysis For caffeine phenotyping subjects will collect all of their urine for 12 hours after receiving the dose to determine CYP1A2 activity AFMU1X1U17U NAT-2 AFMUAFMU1X1U and XO 1U1X1U Urine will be acidified with ascorbic acid in vitro to prevent AFMU conversion
For warfarin phenotyping blood samples will be obtained at 0 3 6 12 24 36 48 72 and 96 hours following warfarin plus vitamin K administration to determine CYP2C9 activity S-warfarin CLF mLmin For the first 12 hours blood will be obtained through an intravenous IV catheter Thereafter it will be via venipuncture
For omeprazole phenotyping one 15 mL blood sample will be drawn 2 hours after the oral omeprazole dose to determine CYP2C19 activity OMP5OH OMP
For dextromethorphan phenotyping subjects will collect all of their urine for 12 hours after receiving the dose to determine CYP2D6 activity DMDX
For midazolam phenotyping use of oral midazolam gives an assessment of inhibition of both gut and hepatic CYP3A
For Phase 1 51 cocktail alone 8 blood samples 10 mL each will be obtained immediately after midazolam administration 0 minute then at 5 minutes 05 1 2 4 5 and 6 hours to determine CYP3A activity MDZ CLF mLmin
During the azithromycin telithromycin and levofloxacin phases blood samples will be collected at 025 075 1 15 2 4 6 8 10 12 and 24 hours to allow for adequate sampling with drugs that potentially inhibit CYP3A
All blood samples except 15 mL for omeprazole will be collected in duplicate in 10 mL EDTA-containing test tubes and centrifuged for 15 minutes at 2800 rpm
Plasma and urine samples will be frozen at -80C until analysis
Data Analysis Caffeine phenotyping assay Urine aliquots will be assayed to determine urinary concentration of 1U 1X 17U and AFMU Urine aliquots will be analyzed at University of Missouri Kansas City Caffeine demethylation ratios will be used to express CYP1A2 NAT-2 and XO activity
S- and R-warfarin phenotyping assay S- and R-warfarin in plasma will be determined utilizing high performance liquid chromatography HPLC analysis at the University of North Carolina Chapel Hill Warfarin clearance will be determined using non-compartmental analysis WinNonlin 31 will be used for pharmacokinetic analyses
Omeprazole phenotyping assay Blood samples will be analyzed at the University of North Carolina Chapel Hill to determine plasma concentrations of OMP and 5OH OMP The ratio of OMP and 5OH OMP at 2 hours following the oral dose of omeprazole will be used to describe CYP2C19 activity
Dextromethorphan phenotyping assay Urine aliquots will be analyzed at University of Missouri Kansas City to determine urinary concentrations of DMDX The dextromethorphan metabolic ratio will be used to describe CYP2D6 activity
Midazolam phenotyping assay Blood samples will be analyzed to determine plasma concentration of midazolam 1-hydroxymidazolam and 4-hydroxymidazolam Analyses will be performed at Oneida Research Services Inc using a proprietary LCMSMS method Midazolam clearance will be used to reflect CYP3A activity and clearance will be determined by using non-compartmental analysis of midazolam plasma concentration-time data WinNonlin 31 will be used for pharmacokinetic analyses
Statistical Analysis
Sample size Using 005 four treatment phases and 020 power of 80 an estimated sample size of sixteen volunteers will detect a 25 difference in metabolism
Data will be analyzed using the FDAs standard bioequivalency testing3 If the drug phases fall outside of the 08-125 range versus the control phase BE will not be shown
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
1 What is the purpose of this study What question is it designed to answer
To compare the effect of azithromycin telithromycin and levofloxacin on activity of 7 hepatic drug metabolizing enzymes using the Cooperstown 51 Cocktail
Background
2 Why is this study important
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 CYP3A45 This combination of probes has been validated in the Cooperstown 51 Cocktail 511 The use of the 51 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 studies2 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 subjects 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 51 Cocktail alone The Cooperstown 51 Cocktail consists of the following components
1 Caffeine 2 mgkg orally rounded to nearest 50 mg with collection of a 12-hour urine
2 Warfarin 10 mg 10 mg vitamin K orally with collection of plasma over 96 hours Plasma collection times are at 0 3 6 12 24 36 48 72 and 96 hours after dosing The INR will be checked at 48 hours If the INR is 17 5 mg of vitamin K will be administered by mouth daily until the INR is 12
3 Omeprazole 40 mg orally with collection of a plasma sample 2 hours after dosing
4 Dextromethorphan 30 mg orally with collection of a 12-hour urine
5 Midazolam 0075 mgkg orally with collection of 8 plasma samples over 6 hours only for Phase 1 to determine CYP3A activity MDZ CLF mLmin Samples will be drawn immediately after midazolam administration 0 minute then at 5 minute 05 1 2 4 5 and 6 hours Breathing heart rate and oxygen saturation will be monitored via pulse oximetry for the first 90 minutes after midazolam dose
Phase 2 Azithromycin 500 mg qAM for 3 days on an empty stomach On day 4 the Cooperstown 51 Cocktail will be administered with a fourth dose of azithromycin given 2 hours after 51 administration
Phase 3 Telithromycin 800 mg qAM for 3 days on an empty stomach On day 4 the Cooperstown 51 Cocktail will be administered with a fourth dose of telithromycin given 2 hours after 51 administration
Phase 4 Levofloxacin 750 mg qAM for 3 days on an empty stomach On day 4 the Cooperstown 51 Cocktail will be administered with a fourth dose of levofloxacin given 2 hours after 51 administration
During the azithromycin telithromycin and levofloxacin phases plasma samples for midazolam will be collected at 025 075 1 15 2 4 6 8 10 12 and 24 hours to allow for adequate sampling with drugs that potentially inhibit CYP3A The 51 cocktail will be administered on day 4 after a minimum of 8-hour fasting
Subjects will not be allowed to eat until 2 hours after administration of study drugs 51 cocktail or antibiotic
Washout periods One week after each phase except for the azithromycin phase is required to ensure the drug is completely eliminated from the body Three weeks after the azithromycin phase is required since azithromycin has a longer half-life
Sample Collection and Analysis For caffeine phenotyping subjects will collect all of their urine for 12 hours after receiving the dose to determine CYP1A2 activity AFMU1X1U17U NAT-2 AFMUAFMU1X1U and XO 1U1X1U Urine will be acidified with ascorbic acid in vitro to prevent AFMU conversion
For warfarin phenotyping blood samples will be obtained at 0 3 6 12 24 36 48 72 and 96 hours following warfarin plus vitamin K administration to determine CYP2C9 activity S-warfarin CLF mLmin For the first 12 hours blood will be obtained through an intravenous IV catheter Thereafter it will be via venipuncture
For omeprazole phenotyping one 15 mL blood sample will be drawn 2 hours after the oral omeprazole dose to determine CYP2C19 activity OMP5OH OMP
For dextromethorphan phenotyping subjects will collect all of their urine for 12 hours after receiving the dose to determine CYP2D6 activity DMDX
For midazolam phenotyping use of oral midazolam gives an assessment of inhibition of both gut and hepatic CYP3A
For Phase 1 51 cocktail alone 8 blood samples 10 mL each will be obtained immediately after midazolam administration 0 minute then at 5 minutes 05 1 2 4 5 and 6 hours to determine CYP3A activity MDZ CLF mLmin
During the azithromycin telithromycin and levofloxacin phases blood samples will be collected at 025 075 1 15 2 4 6 8 10 12 and 24 hours to allow for adequate sampling with drugs that potentially inhibit CYP3A
All blood samples except 15 mL for omeprazole will be collected in duplicate in 10 mL EDTA-containing test tubes and centrifuged for 15 minutes at 2800 rpm
Plasma and urine samples will be frozen at -80C until analysis
Data Analysis Caffeine phenotyping assay Urine aliquots will be assayed to determine urinary concentration of 1U 1X 17U and AFMU Urine aliquots will be analyzed at University of Missouri Kansas City Caffeine demethylation ratios will be used to express CYP1A2 NAT-2 and XO activity
S- and R-warfarin phenotyping assay S- and R-warfarin in plasma will be determined utilizing high performance liquid chromatography HPLC analysis at the University of North Carolina Chapel Hill Warfarin clearance will be determined using non-compartmental analysis WinNonlin 31 will be used for pharmacokinetic analyses
Omeprazole phenotyping assay Blood samples will be analyzed at the University of North Carolina Chapel Hill to determine plasma concentrations of OMP and 5OH OMP The ratio of OMP and 5OH OMP at 2 hours following the oral dose of omeprazole will be used to describe CYP2C19 activity
Dextromethorphan phenotyping assay Urine aliquots will be analyzed at University of Missouri Kansas City to determine urinary concentrations of DMDX The dextromethorphan metabolic ratio will be used to describe CYP2D6 activity
Midazolam phenotyping assay Blood samples will be analyzed to determine plasma concentration of midazolam 1-hydroxymidazolam and 4-hydroxymidazolam Analyses will be performed at Oneida Research Services Inc using a proprietary LCMSMS method Midazolam clearance will be used to reflect CYP3A activity and clearance will be determined by using non-compartmental analysis of midazolam plasma concentration-time data WinNonlin 31 will be used for pharmacokinetic analyses
Statistical Analysis
Sample size Using 005 four treatment phases and 020 power of 80 an estimated sample size of sixteen volunteers will detect a 25 difference in metabolism
Data will be analyzed using the FDAs standard bioequivalency testing3 If the drug phases fall outside of the 08-125 range versus the control phase BE will not be shown
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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None