Ignite Creation Date:
2024-10-26 @ 3:37 PM
Last Modification Date:
2024-10-26 @ 3:37 PM
Study NCT ID:
NCT06549062
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-08-08
Brief Title:
Pharmacokinetics and Pharmacodynamics of Intravenous Paracetamol in Morbidly Obese and Non- Obese Patients
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Pharmacokinetics and Pharmacodynamics of Intravenous ParacetamolAcetaminophen in Morbidly Obese and Non- Obese Patients
Status:
RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 Rongens 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
The primary endpoint of this study is to validate Van Rongens 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
Detailed Description:
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
Recent publications have shown that a higher dose of paracetamol may be required to achieve adequate concentrations in morbidly obese patients due to increased CYP2E1-mediated oxidation of paracetamol Van Rongen et al Clin Pharmacokinet 2016
In contrast the increased CYP2E1 activity will also lead to production of the toxic paracetamol metabolite N-Acetyl-p-benzoquinone imine NAPQI NAPQI forms compounds or adducts with specific liver proteins The concentration of NAPQI adducts correlates with the degree of liver damage and can be considered as a biomarker of potential liver toxicity
Blood sampling is needed to assess plasma concentrations of paracetamol and the NAPQI adducts Recently the Volumetric Absorptive MicroSampling VAMS method has become available as a minimally invasive sampling strategy requiring only 10 µl of capillary blood and has been validated for quantitative analysis of paracetamol and the NAPQI adducts in blood and CSF Delahaye Dhont et al 2019
Specific objectives
The primary endpoint of this study is to validate Van Rongens 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
Methods
The obese cohort group will consist of 40 obese patients undergoing elective laparoscopic bariatric surgery The control group will consist of non-obese patients undergoing laparoscopic GI surgery because laparoscopic surgery can alter the metabolism of paracetamol both study groups will be stratified to achieve an equal gender composition due to gender differences in paracetamol metabolism
Sample size
70 patients in total 15 male control patients 15 female control patients 20 morbidly obese men and 20 morbidly obese women
Inclusion criteria for obese patients
BMI 35 kgm-2 undergoing laparoscopic surgery
Patients 18 years old
ASA physical classification II to III
Inclusion criteria for control patients
Patients 185 BMI 30 kgm-2 undergoing elective laparoscopic surgery Nissen procedure inguinal hernia repair laparoscopic bowel surgery and cholecystectomy
ASA physical classification I to III
Patients 18 yrs
Exclusion criteria for obese and non-obese patients
Renal impairment eGFR 30ml min Liver disease liver enzymes 3X normal values or documented liver pathology in the medical record Patients with Gilbert-Meulengracht syndrome pregnancy Chronic alcohol intake or alcohol use within the last 72 hours Patients treated with drugs known to affect CYP2E1 and UGT UDP-glucuronosyltransferase Chronic malnutrition Paracetamol allergy Clinical study last 30 days
Procedures
After induction a second intravenous catheter for blood sampling is placed in a large vein of the contralateral arm of the first intravenous line and kept patent with a positive pressure needles connector
The paracetamol dose administered is part of the standard of care and is not a study specific intervention All paracetamol will be administered over 15 minutes with a volumetric pump
T0 administration of standard paracetamol 2g dose after induction of anesthesia followed by IV 1g 6hrs postoperatively up to 30 h after first administration
In addition to paracetamol the patients receive a IV- dose of ibuprofen 600mg every 8h and a patient controlled intravenous analgesia pump with piritramide 1mgml
Routine monitoring
Non-invasive blood pressure NIBP electrocardiography ECG pulse oximetry SpO2 with a Surgical Pleth Index SPI module GE-Health care The SPI index is a measure of the balance between nociceptionantinociception
The first group consists of 40 obese patients undergoing elective laparoscopic surgery The control group consists of non-obese patients undergoing laparoscopic GI surgery because laparoscopy can alter paracetamol metabolism Both groups will be stratified to an equal gender composition due to gender differences in paracetamol metabolism all patients receive the same dose of paracetamol a second intravenous catheter for blood sampling is placed in a large vein of the contralateral arm
Liver function AST ALT prothrombin time PT c-glutamyl transpeptidase c-GT and bilirubin will be assessed before and after 30 h of paracetamol administration T 0 and T 30 h
Venous blood samples are collected at the following times
T 0min 15min 30min 45min 60min 90min 120min 180min 240min 300min 360min 24 hours 24 hours 15min 25 hours 30min 27 hours and 30 hours
VAMS VAMS samples are generated from the collected venous blood sample and from capillary blood obtained by a fingerstick Only at T 0 no VAMS are produced from capillary blood
T 30 min 60 min 120 min 180 min 360 min 24h 15 min and 30 hours 7 finger pricks
In addition the VAS pain score and Surgical Pleth index will also be monitored as well as the consumption of piritramide via a patient-controlled intravenous analgesia pump PCIA pump to objectively evaluate pain relief in the current dosing regimen
Visual Analog Scale and Surgical Pleth Index
VAS pain scores are measured at rest and after movement coughing simultaneously with the SPI
VAS T 180min 240min 300min 360min 24h 24h15 25h30min 27h and 30h SPI T 180min 240min 300min 360min 24h 24h15 25h30min 27h and 30h
Patients who are discharged within 24hrs and cannot complete the full measurement cycle are not considered dropouts
statistical analysis
Fisher exact test for Categorical data For continuous data with normal distribution unpaired student t-test or rMANOVA for repeated measures Mann-Whitney test as non-parametric test and to test the AUC 0-8hr for paracetamol metabolites The Wilcoxon rank test to test liver function samples Acetaminophen and metabolite data are analyzed using non-linear mixed effects modelling NONMEM version 72 Bland- Altman and Passing Bablok regression analysis for agreement between techniques
F significance
If this study reveals that 4gday of paracetamol is insufficient to reach therapeutic plasma levels of paracetamol then higher doses of paracetomol might be needed If the results of the VAMS method are comparable to the venous blood samples than future studies can use capillary samples to explore the concentrations of paracetamol and its toxic metabolites when higher doses of paracetamol are administered
G Flowchart
Inclusion criteria for obese patients
BMI 35 kgm-2 undergoing laparoscopic bariatric surgery
Patients 18 years old
ASA physical classification II to III
Inclusion criteria for control patients
Patients 185 BMI 30 kgm-2 undergoing elective laparoscopic surgery Nissen procedure inguinal hernia repair laparoscopic bowel surgery and cholecystectomy
ASA physical classification I to III
Patients 18 yrs
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
Recent publications have shown that a higher dose of paracetamol may be required to achieve adequate concentrations in morbidly obese patients due to increased CYP2E1-mediated oxidation of paracetamol Van Rongen et al Clin Pharmacokinet 2016
In contrast the increased CYP2E1 activity will also lead to production of the toxic paracetamol metabolite N-Acetyl-p-benzoquinone imine NAPQI NAPQI forms compounds or adducts with specific liver proteins The concentration of NAPQI adducts correlates with the degree of liver damage and can be considered as a biomarker of potential liver toxicity
Blood sampling is needed to assess plasma concentrations of paracetamol and the NAPQI adducts Recently the Volumetric Absorptive MicroSampling VAMS method has become available as a minimally invasive sampling strategy requiring only 10 µl of capillary blood and has been validated for quantitative analysis of paracetamol and the NAPQI adducts in blood and CSF Delahaye Dhont et al 2019
Specific objectives
The primary endpoint of this study is to validate Van Rongens 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
Methods
The obese cohort group will consist of 40 obese patients undergoing elective laparoscopic bariatric surgery The control group will consist of non-obese patients undergoing laparoscopic GI surgery because laparoscopic surgery can alter the metabolism of paracetamol both study groups will be stratified to achieve an equal gender composition due to gender differences in paracetamol metabolism
Sample size
70 patients in total 15 male control patients 15 female control patients 20 morbidly obese men and 20 morbidly obese women
Inclusion criteria for obese patients
BMI 35 kgm-2 undergoing laparoscopic surgery
Patients 18 years old
ASA physical classification II to III
Inclusion criteria for control patients
Patients 185 BMI 30 kgm-2 undergoing elective laparoscopic surgery Nissen procedure inguinal hernia repair laparoscopic bowel surgery and cholecystectomy
ASA physical classification I to III
Patients 18 yrs
Exclusion criteria for obese and non-obese patients
Renal impairment eGFR 30ml min Liver disease liver enzymes 3X normal values or documented liver pathology in the medical record Patients with Gilbert-Meulengracht syndrome pregnancy Chronic alcohol intake or alcohol use within the last 72 hours Patients treated with drugs known to affect CYP2E1 and UGT UDP-glucuronosyltransferase Chronic malnutrition Paracetamol allergy Clinical study last 30 days
Procedures
After induction a second intravenous catheter for blood sampling is placed in a large vein of the contralateral arm of the first intravenous line and kept patent with a positive pressure needles connector
The paracetamol dose administered is part of the standard of care and is not a study specific intervention All paracetamol will be administered over 15 minutes with a volumetric pump
T0 administration of standard paracetamol 2g dose after induction of anesthesia followed by IV 1g 6hrs postoperatively up to 30 h after first administration
In addition to paracetamol the patients receive a IV- dose of ibuprofen 600mg every 8h and a patient controlled intravenous analgesia pump with piritramide 1mgml
Routine monitoring
Non-invasive blood pressure NIBP electrocardiography ECG pulse oximetry SpO2 with a Surgical Pleth Index SPI module GE-Health care The SPI index is a measure of the balance between nociceptionantinociception
The first group consists of 40 obese patients undergoing elective laparoscopic surgery The control group consists of non-obese patients undergoing laparoscopic GI surgery because laparoscopy can alter paracetamol metabolism Both groups will be stratified to an equal gender composition due to gender differences in paracetamol metabolism all patients receive the same dose of paracetamol a second intravenous catheter for blood sampling is placed in a large vein of the contralateral arm
Liver function AST ALT prothrombin time PT c-glutamyl transpeptidase c-GT and bilirubin will be assessed before and after 30 h of paracetamol administration T 0 and T 30 h
Venous blood samples are collected at the following times
T 0min 15min 30min 45min 60min 90min 120min 180min 240min 300min 360min 24 hours 24 hours 15min 25 hours 30min 27 hours and 30 hours
VAMS VAMS samples are generated from the collected venous blood sample and from capillary blood obtained by a fingerstick Only at T 0 no VAMS are produced from capillary blood
T 30 min 60 min 120 min 180 min 360 min 24h 15 min and 30 hours 7 finger pricks
In addition the VAS pain score and Surgical Pleth index will also be monitored as well as the consumption of piritramide via a patient-controlled intravenous analgesia pump PCIA pump to objectively evaluate pain relief in the current dosing regimen
Visual Analog Scale and Surgical Pleth Index
VAS pain scores are measured at rest and after movement coughing simultaneously with the SPI
VAS T 180min 240min 300min 360min 24h 24h15 25h30min 27h and 30h SPI T 180min 240min 300min 360min 24h 24h15 25h30min 27h and 30h
Patients who are discharged within 24hrs and cannot complete the full measurement cycle are not considered dropouts
statistical analysis
Fisher exact test for Categorical data For continuous data with normal distribution unpaired student t-test or rMANOVA for repeated measures Mann-Whitney test as non-parametric test and to test the AUC 0-8hr for paracetamol metabolites The Wilcoxon rank test to test liver function samples Acetaminophen and metabolite data are analyzed using non-linear mixed effects modelling NONMEM version 72 Bland- Altman and Passing Bablok regression analysis for agreement between techniques
F significance
If this study reveals that 4gday of paracetamol is insufficient to reach therapeutic plasma levels of paracetamol then higher doses of paracetomol might be needed If the results of the VAMS method are comparable to the venous blood samples than future studies can use capillary samples to explore the concentrations of paracetamol and its toxic metabolites when higher doses of paracetamol are administered
G Flowchart
Inclusion criteria for obese patients
BMI 35 kgm-2 undergoing laparoscopic bariatric surgery
Patients 18 years old
ASA physical classification II to III
Inclusion criteria for control patients
Patients 185 BMI 30 kgm-2 undergoing elective laparoscopic surgery Nissen procedure inguinal hernia repair laparoscopic bowel surgery and cholecystectomy
ASA physical classification I to III
Patients 18 yrs
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None