Association Between Variations in CYP Pheno- and Genotypes and Plasma Concentration of Chlordiazepoxide in the Treatment of Alcohol Withdrawal Symptoms
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Plasma concentration of chlordiazepoxide and metabolites
研究概览
简要总结
The aim of this study is to elucidate if CYP-phenotypes, variations in CYP-genotypes and dose of chlordiazepoxide is correlated to chlordiazepoxide plasma concentrations in patients admitted to Intensive Care or High Dependency Units due to either respiratory insufficiency and/or agitation while treated for alcohol withdrawal symptoms.
详细描述
Pharmacological treatment caries a risk of overdosing and adverse events. Chlordiazepoxide, among other sedative drugs, has been associated with an increased risk of death. Chlordiazepoxide treatment for alcohol withdrawal symptoms will render some patients in need of ventilatory support and ICU admission. Other patients will not obtain the desired effect from the treatment and will be in a state of agitation despite having received high doses of chlordiazepoxide. This individual variation in effect is not predictable and may be explained by variations in the capacity of drug metabolism.
Chlordiazepoxide is extensively metabolized in the liver by hepatic microsomal enzymes and exhibits capacity limited, protein binding sensitive, hepatic clearance. Metabolism is primarily by cytochrome P450 (CYP), especially CYP3A4 and CYP2C19 systems. Evaluation of CYP phenotypes by drug probe phenotyping is extensively used. Midazolam possesses several characteristics that makes it useable as a pharmacological probe for CYP3A activity despite having already received other benzodiazepines. It is metabolized to a primary metabolite exclusively by CYP3A4/3A5.Omeprazole can likewise be used as a pharmacological probe for CYP2C19.
The drug of investigation is chlordiazepoxide, which has been given before study inclusion. After inclusion and during the study period (12 hours), it is not allowed to administer chlordiazepoxide to the patient. In case of abstinence, the recommended therapy is diazepam or propofol.
Blood samples will be collected and plasma concentrations of chlordiazepoxide and metabolites will be analyzed and compared with the amount of chlordiazepoxide administered at inclusion and 12 hours after inclusion.
Independent variables:
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years
- •Treatment with minimum 200 mg chlordiazepoxide for alcohol withdrawal symptoms during hospital admission
- •Acute admittance to ICU or HDU due to respiratory insufficiency, impaired consciousness or agitation.
- •Inclusion possible within 12 h of ICU/HDU admission.
排除标准
- •Allergies to omeprazole/esomeprazole and midazolam
- •Treatment with chlordiazepoxide within the first 12 h after inclusion (from blood samples at inclusion until blood samples 12 h after inclusion)
- •Treatment with omeprazole/esomeprazole within 1 day prior to ICU/HDU admission and within the first 12 h after inclusion.
- •Treatment with midazolam within 1 day prior to ICU/HDU admission
- •Cardiac arrest prior to admission
- •Pregnancy (a negative hcg (from urine or blood sample) has to be present before inclusion of women aged <50 years)
结局指标
主要结局
Plasma concentration of chlordiazepoxide and metabolites
时间窗: At inclusion and 12 hours after inclusion
p-chlordiazepoxide and metabolites.
次要结局
- Half-life (T½) for chlordiazepoxide(At inclusion and 12 hours after inclusion)
- Cumulative dose of chlordiazepoxide before admission to ICU/HDU(From date of hospital admittance until the date of inclusion in the study no later than 12 hours after admission on either ICU or HDU)
- Need for mechanical ventilation within 90 days(90 days after inclusion)
- ICU/HDU and hospital length of stay (LOS) within 90 days(90 days after ICU admission and 90 days after hospital admission)
研究者
Nanna Reiter
Principal investigator
University Hospital Bispebjerg and Frederiksberg