The Effect of Obesity in Dexmedetomidine Metabolic Clearance

Obesity Clinical Trial

Official title:

The Effect of Obesity in Dexmedetomidine Metabolic Clearance

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02557867
• Other study ID #: 14-253
• Secondary ID: 1150197
• Status: Active, not recruiting
• Phase: Phase 4
• First received: September 6, 2015
• Last updated: October 10, 2016
• Start date: August 2015
• Est. completion date: December 2017

Study information

• Verified date: October 2016
• Source: Pontificia Universidad Catolica de Chile
• Contact: n/a
• Is FDA regulated: No
• Health authority: Chile: Comité de Ética CientíficoChile: Instituto de Salud Pública de Chile
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to study the effect of obesity in dexmedetomidine pharmacokinetics and pharmacodynamic profile.

Description:

The investigators expect to find an inverse correlation between the amount of fat mass and liver blood flow or with the enzymatic metabolic capacity. Results will be based on a population pharmacokinetic modeling analysis performed in NONMEM program. The investigators will first account for the effect of different measured size scalars on volumes and clearances and then they will search for plausible covariates (liver blood flow, enzymatic capacity, degree of hepatic steatosis, etc) on dexmedetomidine metabolic clearance. A pharmacokinetic model capable of characterizing clearance changes in the obese using more plausible biological covariates will be tried to be defined.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 40
• Est. completion date: December 2017
• Est. primary completion date: October 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria for obese patients:

• American Society of Anesthesiology classification I-III patients.

• Both genders.

• Age between 18 - 60 years.

• Body mass index higher than 40 Kg/m2.

Inclusion Criteria for non-obese patients:

• American Society of Anesthesiology classification I-II patients

• Both genders.

• Age between 18 - 60 years

• Body mass index lower than 30 Kg/m2.

Exclusion Criteria:

• Known allergy to study drugs

• Uncontrolled hypertension.

• Heart block greater than first degree.

• Chronic hepatic and kidney disease.

• Patients taking any drug acting in the central nervous system within 24 hrs before surgery.

• Patients taking drugs that induce overexpression of liver cytochrome P450-complex enzymes (Carbamazepine, Phenytoin, Phenobarbital, Rifampicin, Dexamethasone, Griseofulvin, Terbinafine, Prednisone, Hydrocortisone, Modafinil).)

• Known addiction to illicit drugs.

• Pregnancy.

• Current or past oncologic disease.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Obesity

Intervention

Drug:
• Dexmedetomidine
Dexmedetomidine 0.5 µg/kg over 10 minutes and then, 0.5 mcg/kg/h throughout surgery.

Locations

Country	Name	City	State
Chile	Hospital Clinico Pontificia Universidad Catolica	Santiago	Región metropolitana

Sponsors (1)

Lead Sponsor	Collaborator
Pontificia Universidad Catolica de Chile

Country where clinical trial is conducted

Chile, 

References & Publications (12)

Bedogni G, Agosti F, De Col A, Marazzi N, Tagliaferri A, Sartorio A. Comparison of dual-energy X-ray absorptiometry, air displacement plethysmography and bioelectrical impedance analysis for the assessment of body composition in morbidly obese women. Eur J Clin Nutr. 2013 Nov;67(11):1129-32. doi: 10.1038/ejcn.2013.159. Epub 2013 Sep 11. — View Citation

Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999 Sep;94(9):2467-74. — View Citation

Casati A, Putzu M. Anesthesia in the obese patient: pharmacokinetic considerations. J Clin Anesth. 2005 Mar;17(2):134-45. Review. — View Citation

Duffull SB, Dooley MJ, Green B, Poole SG, Kirkpatrick CM. A standard weight descriptor for dose adjustment in the obese patient. Clin Pharmacokinet. 2004;43(15):1167-78. — View Citation

Green B, Duffull SB. What is the best size descriptor to use for pharmacokinetic studies in the obese? Br J Clin Pharmacol. 2004 Aug;58(2):119-33. Review. — View Citation

Gurbet A, Basagan-Mogol E, Turker G, Ugun F, Kaya FN, Ozcan B. Intraoperative infusion of dexmedetomidine reduces perioperative analgesic requirements. Can J Anaesth. 2006 Jul;53(7):646-52. — View Citation

Hall JE, Uhrich TD, Barney JA, Arain SR, Ebert TJ. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg. 2000 Mar;90(3):699-705. — View Citation

Han PY, Duffull SB, Kirkpatrick CM, Green B. Dosing in obesity: a simple solution to a big problem. Clin Pharmacol Ther. 2007 Nov;82(5):505-8. — View Citation

Hsu YW, Cortinez LI, Robertson KM, Keifer JC, Sum-Ping ST, Moretti EW, Young CC, Wright DR, Macleod DB, Somma J. Dexmedetomidine pharmacodynamics: part I: crossover comparison of the respiratory effects of dexmedetomidine and remifentanil in healthy volunteers. Anesthesiology. 2004 Nov;101(5):1066-76. — View Citation

Ji QC, Zhou JY, Gonzales RJ, Gage EM, El-Shourbagy TA. Simultaneous quantitation of dexmedetomidine and glucuronide metabolites (G-Dex-1 and G-Dex-2) in human plasma utilizing liquid chromatography with tandem mass spectrometric detection. Rapid Commun Mass Spectrom. 2004;18(15):1753-60. — View Citation

Kaivosaari S, Toivonen P, Aitio O, Sipilä J, Koskinen M, Salonen JS, Finel M. Regio- and stereospecific N-glucuronidation of medetomidine: the differences between UDP glucuronosyltransferase (UGT) 1A4 and UGT2B10 account for the complex kinetics of human liver microsomes. Drug Metab Dispos. 2008 Aug;36(8):1529-37. doi: 10.1124/dmd.108.021709. Epub 2008 May 12. — View Citation

Li W, Zhang Z, Wu L, Tian Y, Feng S, Chen Y. Determination of dexmedetomidine in human plasma using high performance liquid chromatography coupled with tandem mass spectrometric detection: application to a pharmacokinetic study. J Pharm Biomed Anal. 2009 Dec 5;50(5):897-904. doi: 10.1016/j.jpba.2009.06.012. Epub 2009 Jun 16. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dexmedetomidine plasmatic levels	Measured by high performance liquid chromatography	From start of infusion (min): 5, 10, 20, 30, 45, 60, 90, 120, 150, 180; from end of infusion (min): 5, 10, 20, 30, 60, 90, 120, 240, 360, 720	No
Secondary	Steatohepatitis score	Using liver biopsy, a score for steatohepatitis will be applied on samples from all patients	3 months after liver biopsy specimen collection	No
Secondary	Plasma disappearance rate of indocyanine	Using indocyanine green and LiMON monitor (Pulsion Medical Systems) surrogate measures of liver blood flow will be registered.	2 hours after arrival to Post-Anesthesia Care Unit	No
Secondary	Enzyme expression	Liver samples will be analyzed for UGT2B10 and UGT1A4 expression (involved in dexmedetomidine metabolization)	3 months after liver biopsy specimen collection	No
Secondary	Hemodynamics	Heart rate and arterial pressure will be recorded during anesthesia	Recorded at every blood sample collection (5, 10, 20, 30, 45, 60, 90, 120, 150, 180 min) during anesthesia	Yes
Secondary	Anesthetic depth	Using a bispectral index monitor, anesthetic depth will be monitorized through out surgery.	Recorded at every blood sample collection (5, 10, 20, 30, 45, 60, 90, 120, 150, 180 min) during anesthesia	Yes