Pharmacokinetics and Pharmacodynamics of Intravenous Paracetamol in Morbidly Obese and Non- Obese Patients.

NCT06549062 | Recruiting

• 1 other identifier: BC-07469
• Study Type: observational
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acetaminophen Toxicity; Obesity, Morbid

Keywords

acetaminophen pharmacokinetics; obesity; NAPQI protein adducts; CYP 2E1

Outcome Measures

Primary Outcomes (10)

• acetaminophen

  plasma concentrations and capillary blood concentrations

  first six hours after IV administration of the loading dose of 2g

• acetaminophen

  plasma concentrations and capillary blood concentrations

  the six hours after IV administration of the fifth dose of 1g acetaminophen

• acetaminophen-glucuronide metabolite

  plasma concentrations and capillary blood concentrations

  the first six hours after IV administration of a loading dose of 2g acetaminophen

• acetaminophen-glucuronide metabolite

  plasma concentrations and capillary blood concentrations

  the first six hours after IV administration of fifth dose of 1 g acetaminophen

• acetaminophen-sulphate metabolite

  plasma concentrations and capillary blood concentrations

  the first six hours after IV administration of 2g IV acetaminophen

• acetaminophen-sulphate metabolite

  plasma concentrations and capillary blood concentrations

  the six hours after IV administration of fifth dose of 1g IV acetaminophen

• acetaminophen- Cysteine protein adduct

  plasma concentrations and capillary blood concentrations

  the first six hours after IV administration of 2 g loading dose of acetaminophen

• acetaminophen- Cysteine protein adduct

  plasma concentrations and capillary blood concentrations

  the six hours after IV administration of the fifth dose of 1g acetaminophen

• acetaminophen- mercapturate protein adduct

  plasma concentrations and capillary blood concentrations

  the first six hours after IV administration loading dose 2g acetaminophen

• acetaminophen- mercapturate protein adduct

  plasma concentrations and capillary blood concentrations

  the six hours after IV administration of the fifth dose of 1g acetaminophen

Secondary Outcomes (5)

• pain score using Visual analog scale at rest

  hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30

• 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

• patient controlled intravenous analgesia: piritramide consumption

  first 30 hours after starting acetaminophen or until discharge from the hospital

Study Arms (2)

obese patients WHO class > 2

patients with a BMI \> 35 undergoing laparoscopic surgery. venous and capillary blood samples are collected to determine the concentrations of acetaminophen and its metabolites after intravenous administration of a first dose of 2g acetaminophen and after a fifth dose of 1g acetaminophen in steady state conditions.

non obese and overweight patients

patients with a BMI between 18,5 - 30 undergoing laparoscopic surgery. Venous and capillary blood samples are collected to determine the concentrations of acetaminophen and its metabolites after intravenous administration of a first dose of 2g acetaminophen and after a fifth dose of 1g acetaminophen in steady state conditions.

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

control group is the cohort of patients with a BMI between 18,5 and 30 kg/m2. study group is the cohort of patients with a BMI over 35 kg/m2. All patients undergo laparscopic surgery because laparoscopy can affect liver function. since there are gender differences in acetaminophen metabolism, both cohorts were stratified into equal amounts of men and women.

You may qualify if:

• 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

You may not qualify if:

• 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
• Pregnancy

Sponsors & Collaborators

• University Hospital, Ghent: lead

Study Sites (1)

University Hospital

Ghent, Oost-Vlaanderen, 9000, Belgium

RECRUITING

Related Publications (1)

• van Rongen A, Valitalo PAJ, Peeters MYM, Boerma D, Huisman FW, van Ramshorst B, van Dongen EPA, van den Anker JN, Knibbe CAJ. Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen. Clin Pharmacokinet. 2016 Jul;55(7):833-847. doi: 10.1007/s40262-015-0357-0.

  PMID: 26818482 RESULT

Biospecimen

Retention: SAMPLES WITHOUT DNA

venous blood samples with simultaneous synchronised capillary blood samples

MeSH Terms

Conditions

Obesity, Morbid; Obesity

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Luc De Baerdemaeker, Md,PhD

  University Hospital, Ghent

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Luc De Baerdemaeker, MD, PhD

CONTACT

09 332 3281; luc.debaerdemaeker@ugent.be

Ann De Bruyne, study nurse

CONTACT

09332 3281; ann.debruyne@ugent.be

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: head of department

Study Record Dates

• First Submitted: August 8, 2024
• First Posted: August 12, 2024
• Study Start: September 11, 2020
• Primary Completion: January 1, 2025
• Study Completion: January 1, 2025
• Last Updated: August 12, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)