Evaluation of the Potential Pharmacokinetic Interactions Between Probe Drugs in the Geneva Phenotyping Cocktail
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Area under the capillary blood concentration-time curve (AUC) of flurbiprofen
研究概览
简要总结
Phenotyping is an approach largely used for the evaluation of the activity of cytochromes and transporters in vivo. It consists of the administration of probe substances metabolised by a specific cytochrome or transported by P-glycoprotein (P-gp) for example, followed by the determination of a metabolic ratio or the evaluation of the plasmatic or urinary concentrations of the probe substances. The administration of a cocktail containing several probe substances allows the simultaneous evaluation of the activity of several cytochromes and P-gp in a single test.
When a cocktail approach is used it is important to make sure that no drug-drug interactions occur between the probes within the cocktail. The validation of the lack of interactions, which is the aim of the study, consists of demonstrating that there is no difference in the pharmacokinetic parameters and/or metabolic ratios when a probe is administered alone or as part of the cocktail. The Geneva cocktail consists of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam and fexofenadine for the simultaneous phenotyping of CYP1A2, CYP2B6, CYP2C9, CAP2C19, CYP2D6, CYP3A4 and P-gp, respectively.
Probe and metabolite concentrations will be measured in capillary blood using a dried blood spot (DBS) analysis. To further facilitate sampling, a new simple device will be used to ensure the precision of capillary blood collection.
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 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy volunteers aged from 18 to 60 years
- •BMI between 18 and 27
- •Understanding of French language and able to give a written inform consent.
排除标准
- •pregnant women
- •taking drugs which alter cytochrome P450 (CYP) activity
- •renal or hepatic impairment
- •medical history of chronic alcoholism or abuse of psychoactive drugs
- •liver transplantation
- •sensitivity to any of the drugs used
- •Alteration of hepatic tests, more than 2x normal (aspartate transaminase >100U/L ; alanine transaminase >100 units/L ; gamma-glutamyl transferase >80 units/L ; bilirubin >50µmol/L)
- •Presenting genetic polymorphism of poor CYP2C9, CYP2C19, CYP2D6 metabolizer
研究组 & 干预措施
Treatment A
Oral intake of:
caffeine 50 mg dextromethorphan 10 mg omeprazole 10 mg flurbiprofen 10 mg midazolam 1 mg
干预措施: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam (Drug)
Treatment D
Oral Intake of Geneva cocktail (A+B+C):
caffeine 50 mg dextromethorphan 10 mg omeprazole 10 mg flurbiprofen 10 mg midazolam 1 mg fexofenadine 25 mg bupropion 20 mg
干预措施: Bupropion (Drug)
Treatment B
Oral intake of:
fexofenadine 25 mg
干预措施: Fexofenadine (Drug)
Treatment C
Oral intake of:
bupropion 20 mg
干预措施: Bupropion (Drug)
Treatment D
Oral Intake of Geneva cocktail (A+B+C):
caffeine 50 mg dextromethorphan 10 mg omeprazole 10 mg flurbiprofen 10 mg midazolam 1 mg fexofenadine 25 mg bupropion 20 mg
干预措施: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam (Drug)
Treatment D
Oral Intake of Geneva cocktail (A+B+C):
caffeine 50 mg dextromethorphan 10 mg omeprazole 10 mg flurbiprofen 10 mg midazolam 1 mg fexofenadine 25 mg bupropion 20 mg
干预措施: Fexofenadine (Drug)
结局指标
主要结局
Area under the capillary blood concentration-time curve (AUC) of flurbiprofen
时间窗: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Comparison of flurbiprofen AUC when treatment A or D is administered
Area under the capillary blood concentration-time curve (AUC) of midazolam
时间窗: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Comparison of midazolam AUC when treatment A or D is administered
Area under the capillary blood concentration-time curve (AUC) of dextromethorphan
时间窗: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Comparison of dextromethorphan AUC when treatment A or D is administered
Area under the capillary blood concentration-time curve (AUC) of bupropion
时间窗: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post treatment C or D
Comparison of bupropion AUC when treatment C or D is administered
Area under the capillary blood concentration-time curve (AUC) of caffeine
时间窗: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Comparison of caffeine AUC when treatment A or D is administered
Area under the capillary blood concentration-time curve (AUC) of omeprazole
时间窗: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Comparison of omeprazole AUC when treatment A or D is administered
Area under the capillary blood concentration-time curve (AUC) of fexofenadine
时间窗: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment B or D
Comparison of fexofenadine AUC when treatment B or D is administered
次要结局
- Metabolic ratio (MR) of 1-hydroxymidazolam blood concentration /midazolam blood concentration(0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D)
- Metabolic ratio (MR) of 4-hydroxyflurbiprofen blood concentration /flurbiprofen blood concentration(0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D)
- Metabolic ratio (MR) of 5-hydroxyomeprazole blood concentration /omeprazole blood concentration(0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D)
- Number of adverse events(at each drug administration day)
- Metabolic ratio (MR) of paraxanthine blood concentration /caffeine blood concentration(0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D)
- Metabolic ratio (MR) of 4-hydroxybupropion blood concentration /bupropion blood concentration(0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post treatment C or D)
- Metabolic ratio (MR) of dextrorphan blood concentration /dextromethorphan blood concentration(0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D)
研究者
Jules Desmeules
Professor
University Hospital, Geneva