Clinical trial NCT02399397: Influence of Age, Sepsis and SLCO1A2 Polymorphisms on Rocuronium Pharmacokinetics
Official title: Influence of Sepsis, Age and SLCO1A2 Genetic Polymorphisms on Rocuronium Pharmacokinetics-pharmacodynamics in ASA I-III Surgical Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Sepsis
Systemic Inflammatory Response Syndrome
Septic Shock
Lead sponsor: Universidade Estadual Paulista Júlio de Mesquita Filho
Sponsor class: OTHER
Collaborators: name: University of Sao Paulo
First posted: 2015-03-26
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Determination of AUC/dose
timeFrame: Up to 6h after rocuronium administration
Secondary outcomes:
measure: Determination of total clearance
timeFrame: Up to 6h after rocuronium administration
measure: Determination of volume of distribution
timeFrame: Up to 6h after rocuronium administration
measure: Determination of mean residence time
timeFrame: Up to 6h after rocuronium administration
measure: OATP1A2 genotyping using Real Time-PCR
timeFrame: Up to 5 minutes before rocuronium administration
measure: Analysis of cytokine IL-1α in plasma
timeFrame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
measure: Analysis of cytokine IL-1β in plasma
timeFrame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
measure: Analysis of cytokine IL-6 in plasma
timeFrame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
measure: Analysis of cytokine TNF-α in plasma
timeFrame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
measure: Pharmacokinetic-Pharmacodynamic analysis: relationship between rocuronium plasma concentration and the neuromuscular blockade
timeFrame: Up to 6h after rocuronium administration
Other outcomes:
Locations:
city: Araraquara
country: Brazil
facility: Universidade Estadual Paulista Júlio de Mesquita Filho
state: São Paulo
Study officials:
affiliation: Universidade Estadual Paulista Júlio de Mesquita Filho
name: Natalia V. de Moraes, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.