Influence of Age, Sepsis and SLCO1A2 Polymorphisms on Rocuronium Pharmacokinetics (ROCSEPSIS)

Influence of Sepsis, Age and SLCO1A2 Genetic Polymorphisms on Rocuronium Pharmacokinetics-pharmacodynamics in ASA I-III Surgical Patients

This study aims to evaluate the influence of age and sepsis on in vivo activity of OATP1A2 using rocuronium (ROC) as a probe and evaluating the pharmacokinetics and pharmacodynamics in ASA I-III surgical patients. Thus, adult patients without sepsis (control group, n= 12), adult patients with sepsis (sepsis group, n= 12) and elderly patients without sepsis (elderly group, n= 12), all submitted to small to medium-sized surgeries who were induced with individual doses of rocuronium, fentanyl and propofol are being investigated.

Study Overview

• Status: Completed
• Conditions: Sepsis; Systemic Inflammatory Response Syndrome; Septic Shock
• Intervention / Treatment: Procedure: Serial blood sampling; Procedure: Train of four monitoring; Procedure: Blood testing for liver and renal function; Drug: General anesthesia; Procedure: Small to medium sized surgery under general anesthesia

Detailed Description

Rocuronium (ROC), a neuromuscular blocking agent used in surgical procedures, is primarily eliminated by biliary excretion. Its distribution to the liver, mediated the organic anion transporting polypeptide 1A2 (OATP1A2), is a determining factor for the duration of neuromuscular blockade. Age and release of cytokines during inflammation and infection processes of sepsis can alter expression of SLCO1A2 gene, encoding OATP1A2. The objective of this study is to evaluate the influence of age and sepsis on in vivo activity of OATP1A2 using ROC as a probe and evaluating the pharmacokinetics and pharmacodynamics in ASA I-III surgical patients. Adult patients without sepsis (control group, n=12), adult patients with sepsis (sepsis group, n=12) and elderly patients without sepsis (elderly group, n=12), all submitted to small to medium-sized surgeries are being investigated. All patients are being induced with individual doses of rocuronium, fentanyl and propofol. Serial blood samples are being collected up to 360 minutes after administration of ROC. Neuromuscular blockade induced by ROC is monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same times of blood sampling. The plasma concentration of ROC will be analyzed by liquid chromatography coupled to mass spectrometry with electrospray ionization using positive ion mode.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • São Paulo
    • Araraquara, São Paulo, Brazil, 14801902
      • Universidade Estadual Paulista Júlio de Mesquita Filho

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult and elderly patients, both gender.
• Patients submitted to small to medium-sized surgeries.
• Patients who were induced with individual doses of rocuronium, fentanyl and propofol.
• Patients with normal renal function (creatinine clearance > 60 mL/min).
• Patients with normal liver function.

Exclusion Criteria:

• Patients who were in use of fluoxetine, carbamazepine, aminoglycoside antibiotics, OATP1A2 inhibitors.
• Patients with gastrointestinal and liver diseases, neuromuscular disorders.
• Patients who were in chronic use of drugs which alter rocuronium effect.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control group; Adult patients(18-50 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).	Procedure: Serial blood sampling; Serial blood samples are being collected at times 0, 2, 5, 10, 15, 20, 30, 60, 120, 180, 240 and 360 minutes after rocuronium administration.; Procedure: Train of four monitoring; Neuromuscular blockade is being evaluated at the same time of blood sampling by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF).; Other Names: TOF; Procedure: Blood testing for liver and renal function; Blood testing: urea, creatinine, aspartate aminotransferase, alanine aminotransferase, albumin, glycemia; Drug: General anesthesia; All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol.; Other Names: Fentanyl; Midazolam; Rocuronium; Propofol; Procedure: Small to medium sized surgery under general anesthesia; Patients classified according American Society of Anesthesiologists (ASA) as ASA I-III and submitted to small-medium sized surgery under general anesthesia were recruited for the present investigation.
Experimental: Sepsis group; Adult patients (18-50 years old) ASAII and III with sepsis, systemic inflammatory response syndrome or septic shock submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).	Procedure: Serial blood sampling; Serial blood samples are being collected at times 0, 2, 5, 10, 15, 20, 30, 60, 120, 180, 240 and 360 minutes after rocuronium administration.; Procedure: Train of four monitoring; Neuromuscular blockade is being evaluated at the same time of blood sampling by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF).; Other Names: TOF; Procedure: Blood testing for liver and renal function; Blood testing: urea, creatinine, aspartate aminotransferase, alanine aminotransferase, albumin, glycemia; Drug: General anesthesia; All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol.; Other Names: Fentanyl; Midazolam; Rocuronium; Propofol; Procedure: Small to medium sized surgery under general anesthesia; Patients classified according American Society of Anesthesiologists (ASA) as ASA I-III and submitted to small-medium sized surgery under general anesthesia were recruited for the present investigation.
Experimental: Elderly group; Elderly patients (> 65 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).	Procedure: Serial blood sampling; Serial blood samples are being collected at times 0, 2, 5, 10, 15, 20, 30, 60, 120, 180, 240 and 360 minutes after rocuronium administration.; Procedure: Train of four monitoring; Neuromuscular blockade is being evaluated at the same time of blood sampling by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF).; Other Names: TOF; Procedure: Blood testing for liver and renal function; Blood testing: urea, creatinine, aspartate aminotransferase, alanine aminotransferase, albumin, glycemia; Drug: General anesthesia; All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol.; Other Names: Fentanyl; Midazolam; Rocuronium; Propofol; Procedure: Small to medium sized surgery under general anesthesia; Patients classified according American Society of Anesthesiologists (ASA) as ASA I-III and submitted to small-medium sized surgery under general anesthesia were recruited for the present investigation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of AUC/dose	Determination of area under the plasma concentration versus time curve (AUC)/dose of rocuronium will be estimated for pharmacokinetic analysis.	Up to 6h after rocuronium administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of total clearance	Determination of total clearance of rocuronium will be estimated for pharmacokinetic analysis.	Up to 6h after rocuronium administration
Determination of volume of distribution	Determination of volume of distribution of rocuronium will be estimated for pharmacokinetic analysis.	Up to 6h after rocuronium administration
Determination of mean residence time	Determination of mean residence time of rocuronium will be estimated for pharmacokinetic analysis.	Up to 6h after rocuronium administration
OATP1A2 genotyping using Real Time-PCR	The single nucleotide polymorphisms of SLCO1A2 gene (404A>T, 559G>A, 833delA at coding sequence and -1105G>A, -1032G>A, -715T>C, -361G>A e -189_-188insA at the non-coding sequence of SLCO1A2) are being evaluated in all included patients, using Real Time PCR.	Up to 5 minutes before rocuronium administration
Analysis of cytokine IL-1α in plasma	Plasma cytokine Interleukin-1α (IL-1α) will be evaluated in each patient.	Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Analysis of cytokine IL-1β in plasma	Plasma cytokine IL-1β will be evaluated in each patient.	Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Analysis of cytokine IL-6 in plasma	Plasma cytokine IL-6 will be evaluated in each patient.	Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Analysis of cytokine TNF-α in plasma	Plasma cytokine Tumor Necrosis Factor-α (TNF-α) will be evaluated in each patient.	Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Pharmacokinetic-Pharmacodynamic analysis: relationship between rocuronium plasma concentration and the neuromuscular blockade	The relationship between rocuronium plasma concentration and the neuromuscular blockade will be described by a sigmoid maximum effect model for each patient	Up to 6h after rocuronium administration

Collaborators and Investigators

• Sponsor: Universidade Estadual Paulista Júlio de Mesquita Filho
• Collaborators: University of Sao Paulo
• Investigators: Principal Investigator: Natalia V. de Moraes, Prof., Universidade Estadual Paulista Júlio de Mesquita Filho

Publications and helpful links

General Publications

• de Moraes NV, Lauretti GR, Filgueira GC, Lopes BC, Lanchote VL. Analysis of rocuronium in human plasma by liquid chromatography-tandem mass spectrometry with application in clinical pharmacokinetics. J Pharm Biomed Anal. 2014 Mar;90:180-5. doi: 10.1016/j.jpba.2013.11.032. Epub 2013 Dec 7.
• Costa ACC, Coelho EB, Lanchote VL, Correia BV, Abumansur JT, Lauretti GR, de Moraes NV. The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries. Eur J Clin Pharmacol. 2017 Aug;73(8):957-963. doi: 10.1007/s00228-017-2243-1. Epub 2017 Apr 14.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: March 2, 2015
• First Submitted That Met QC Criteria: March 20, 2015
• First Posted (Estimate): March 26, 2015

Study Record Updates

• Last Update Posted (Estimate): January 25, 2017
• Last Update Submitted That Met QC Criteria: January 24, 2017
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Inflammation; Shock; Sepsis; Toxemia; Systemic Inflammatory Response Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Neuromuscular Agents; Neuromuscular Nondepolarizing Agents; Neuromuscular Blocking Agents; Anesthetics; Fentanyl; Midazolam; Propofol; Rocuronium
• Other Study ID Numbers: ROC1314730-0