Comparison of the Effect of Azithromycin, Telithromycin and Levofloxacin on Drug Metabolizing Enzymes Using the Validated Cooperstown 5+1 Cocktail
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 16
- 主要终点
- Phenotype measures
研究概览
简要总结
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.
详细描述
Specific Aims
- 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 5+1 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 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy adults between the ages of 18 and 55 years.
- •Ability to provide written informed consent.
- •Willing to avoid all medications (other than the study drugs) which may inhibit or induce hepatic microsomal enzymes during the study period. This includes prescription and non-prescription medications, vitamins, herbal supplements, and nutriceuticals.
- •Willing to avoid drinking more than the equivalence of one beer per day (one 12 ounce beer or equivalent alcohol intake) throughout the study period.
- •Women of child-bearing potential who are willing to practice non-hormonal methods of contraception during all study phases.
- •Willing to adhere to dietary restrictions as required during the study.
排除标准
- •Clinically significant abnormal findings by history, physical exam, ECG, or laboratory testing.
- •Elevated liver function tests twice above the upper limit of the normal range (males AST 0-50 U/L, ALT 0-60 U/L, GGT 11-50; females AST 0-40 U/L, ALT 0-50 U/L, GGT 7-32), or total bilirubin >1.3mg/dL.
- •Baseline INR >1.
- •Serum creatinine above the normal ranges
- •Women who are pregnant, breastfeeding, and/or not using an acceptable form of non-hormonal contraception (barrier method or abstinence) during the study.
- •History of gastrointestinal bleeding or peptic ulcer disease.
- •Any condition that may affect drug absorption (e.g., gastrectomy, malabsorption syndromes).
- •History of known hypersensitivity or serious adverse reaction to azithromycin, telithromycin, levofloxacin, midazolam, dextromethorphan, caffeine, omeprazole, heparin, warfarin, or vitamin K.
- •Poor IV access as determined by an investigator.
- •Current illicit drug use.
- •History of tobacco use within 3 months of screening.
- •Use of any drug known to inhibit or induce hepatic enzymes within 30 days of the first study phase.
- •Regular alcohol intake exceeding 1 drink/day (1 drink = 5 ounces of wine or 12 ounces of beer or 1 ounce of hard liquor) within 1 months of screening.
- •Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study drug.
- •Presence of any condition that the investigator feels would interfere with successful completion of the study.
- •Poor metabolizers of CYP2D6, CYP2C9, and CYP2C19.
结局指标
主要结局
Phenotype measures
次要结局
未报告次要终点