Pharmacokinetics and Pharmacodynamics of Intravenous Paracetamol/Acetaminophen in Morbidly Obese and Non- Obese Patients.
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- acetaminophen- Cysteine protein adduct
研究概览
简要总结
Obese patients may need higher doses of acetaminophen (APAP) for adequate analgesia, due to increased total clearance and distribution volume. APAP-induced hepatotoxicity is mainly caused through CYP2E1 pathway. Its activity is induced by obesity, potentially endangering the safety profile of APAP. Metabolic-dysfunction associated liver disease (MASLD) is an important associated risk factor for APAP induced-hepatotoxicity.
The primary endpoint of this study is to validate Van Rongen's prediction model on plasma concentration of paracetamol and its metabolites and extend it to the steady state phase over a period of 30 hours by measuring plasma concentrations of paracetamol and its metabolites and comparing them with the plasma concentrations predicted by the model by Van Rongen et al.
In addition, results obtained from venous blood will be compared with results obtained via VAMS after finger stick. If VAMS correlates well with plasma concentrations of paracetamol and its NAPQI adducts, future interventional studies may utilize the patient-friendly VAMS technology in an effort to further investigate the safety and efficacy of higher doses of paracetamol in obese patients and possibly other patient groups.
The secondary endpoints of this study are liver function tests before and after 30hrs of paracetamol administration, the VAS pain scores, the surgical pleth index (SPI) and the consumption of piritramide as recorded by a PCIA pump.
详细描述
A. Pharmacokinetics and pharmacodynamics of Intravenous Paracetamol in morbidly obese and non- obese patients.
Study design: interventional, stratified, controlled, prospective cohort trial
B. Hypothesis morbidly obese patients have increased CYP2E1-mediated oxidation of paracetamol, requiring higher dosage to achieve therapeutic concentrations. Higher CYP2E1 activity will produce more of the toxic NAPQI. The concentration of NAPQI adducts are a biomarker of potential liver toxicity. We expect to find ineffective plasma paracetamol concentrations + higher NAPQI adducts in the venous blood samples of obese patients compared to the non-obese patients, as confirmed by Volumetric absorptive microsampling (VAMS) from capillary blood. Based on our results, future studies can explore higher paracetamol dosage in obese using capillary sampling methods.
C. Background:
Paracetamol still is the cornerstone of non-opioid analgesia in the obese patient. Current dosing recommendations for acetaminophen limit the adult dose to 4g / day regardless of an obese body constitution.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult ≥ 18 < 70 years old (obese patients) Adult ≥ 18 years old (non-obese patients)
- •Able to comprehend, sign, and date the written informed consent document to participate in the clinical trial
- •Obese scheduled for laparoscopic bariatric surgery Non obese scheduled for laparoscopic surgery
- •Control group BMI ≥18.5 en <30 kg.m-2 or Obese group BMI > 35kg.m-2
- •ASA Class I, II or III as assigned by the anaesthesiologist
排除标准
- •Allergy or inability to tolerate "paracetamol"
- •Documented Liver disease or liver enzymes > 3X normal value
- •Kidney disease (eGFR < 30ml.min-1)
- •Participation in a clinical trial within the past 30 days
- •Chronic alcohol abuse or alcohol intake <72hrs
- •Gilbert-Meulengracht-syndroom
- •Chronic malnutrition
- •Intake of medication with influence on CYP2E1 or UDP-glucuronosyltransferase
结局指标
主要结局
acetaminophen- Cysteine protein adduct
时间窗: the six hours after IV administration of the fifth dose of 1g acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen- mercapturate protein adduct
时间窗: the six hours after IV administration of the fifth dose of 1g acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen
时间窗: the six hours after IV administration of the fifth dose of 1g acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen-sulphate metabolite
时间窗: the six hours after IV administration of fifth dose of 1g IV acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen-glucuronide metabolite
时间窗: the first six hours after IV administration of fifth dose of 1 g acetaminophen
plasma concentrations and capillary blood concentrations
次要结局
- pain score using Visual analog scale at rest(hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30)
- patient controlled intravenous analgesia: piritramide consumption(first 30 hours after starting acetaminophen or until discharge from the hospital)
- pain score using Visual analog scale after movement(hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30)
- surgical pleth index (SPI) at rest(hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30)
- surgical pleth index (SPI) after movement(hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30)
研究者
Patrick F Wouters, MD PhD
head of department
University Hospital, Ghent