Influence of Age, Sepsis and SLCO1A2 Polymorphisms on Rocuronium Pharmacokinetics

Sepsis Clinical Trial

— ROCSEPSIS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02399397
• Other study ID #: ROC1314730-0
• Status: Completed
• Phase: Phase 4
• First received: March 2, 2015
• Last updated: January 24, 2017
• Start date: February 2014
• Est. completion date: December 2015

Study information

• Verified date: October 2016
• Source: Universidade Estadual Paulista Júlio de Mesquita Filho
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Sepsis
• Septic Shock
• Shock, Septic
• Systemic Inflammatory Response Syndrome
• Toxemia

Intervention

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.
• 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).
• 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.

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.

Locations

Country	Name	City	State
Brazil	Universidade Estadual Paulista Júlio de Mesquita Filho	Araraquara	São Paulo

Sponsors (2)

Lead Sponsor	Collaborator
Universidade Estadual Paulista Júlio de Mesquita Filho	University of Sao Paulo

Country where clinical trial is conducted

Brazil, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Determination of total clearance	Determination of total clearance of rocuronium will be estimated for pharmacokinetic analysis.	Up to 6h after rocuronium administration
Secondary	Determination of volume of distribution	Determination of volume of distribution of rocuronium will be estimated for pharmacokinetic analysis.	Up to 6h after rocuronium administration
Secondary	Determination of mean residence time	Determination of mean residence time of rocuronium will be estimated for pharmacokinetic analysis.	Up to 6h after rocuronium administration
Secondary	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
Secondary	Analysis of cytokine IL-1a in plasma	Plasma cytokine Interleukin-1a (IL-1a) will be evaluated in each patient.	Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Secondary	Analysis of cytokine IL-1ß in plasma	Plasma cytokine IL-1ß will be evaluated in each patient.	Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Secondary	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
Secondary	Analysis of cytokine TNF-a in plasma	Plasma cytokine Tumor Necrosis Factor-a (TNF-a) will be evaluated in each patient.	Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Secondary	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