Pharmacokinetics of dexmedetomidine in elderly patients undergoing sedation after abdominal aortic surgery.
Agnieszka Bienert (1) Pawel Wiczling (2) Justyna Mocarska (1) Lukasz Zuranski (3) Malgorzata Nowicka (3) Roma Hartmann-Sobczynska (3) Marcin Holysz (4) Jan Matysiak (5) Agnieszka Klupczynska (5) Edmund Grzeskowiak (1) Pawel Sobczynski (3)
Institution: (1) Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Poznan, Poland, (2) Department of Biopharmacy and Pharmacodynamics, Medical University of Gdansk, Gdansk, Poland, (3) Department of Anesthesiology, Intensive Therapy and Pain Treatment, Poznan University of Medical Sciences, Poznan, Poland, (4) Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland, (5) Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, Poznan, Poland
Objectives: Dexmedetomidine (DEX) is an α2-agonist which has been increasingly used for analgosedation. The aim of this study was to characterize the population pharmacokinetics (PK) of dexmedetomidine in patients undergoing sedation after abdominal aortic surgery and to investigate the potential benefits of individualization of drug dosing based on patients’ characteristics including genetic polymorphism. DEX is a highly extracted drug with the hepatic extraction ratio of 0,7 [1], therefore cardiac index and other cardiovascular parameters were also taken into account as potential covariates.
Methods: Dexmedetomidine (Dexdor, Orion Pharma Poland Sp. z.o.o.) was administered by continuous intravenous infusion without a loading dose. The infusion was started at the rate of 0.7 μg/kg/h and titrated to achieve the desired level of sedation according to the monitored bispectral index (BIS, Philips Medical Systems B.V, Netherlands). BIS values were kept between 60 and 80. Cardiac index (CI), a hemodynamic parameter related to cardiac output was measured and recorded by FloTrac System (Edwards Lifescences, USA). Blood samples for DEX assay were collected daily during the infusion and at the selected time points after its termination. The DEX concentrations in the plasma were measured using LC-MS/MS method. The following covariates were examined to influence DEX PK: patients’ age, sex, body weight, systolic and diastolic blood pressure, heart rate, cardiac index, infusion duration as well as CYP2C19, CYP1A2, CYP2A6, UGT1A4 and UGT2B genetic polymorphism. Non-linear mixed-effects modelling in NONMEM (Version 7.3.0, Icon Development Solutions, Ellicott City, MD, USA) was used to analyze the observed data.
Results: Concentration-time profiles of DEX were obtained from 11 male and 1 female elderly patients, with the median age of 64.5 (range between 61 and 79 years). Duration of infusion was less than 24 hours in all patients. The DEX PK was best described by a two-compartment model. The typical values of PK parameters were estimated as 53.4 L for the volume of the central compartment, 112 L for the volume of the peripheral compartment, 51.1 L/h (for a 70 kg patient) for systemic clearance and 36.7 L/h for the distribution clearance. Those values are consistent with literature findings. We were unable to show any significant relationship between collected covariates and DEX PK.
Conclusions: This study does not provide sufficient evidence to support the individualization of DEX dosing based on age, sex, body weight, cardiac index, examined CYP and UGT enzymes polymorphism and infusion duration.
References:
[1] Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clin Pharmacokinet (2017) 56(8): 893–913.
The project was supported by the Grant 2015/17/B/NZ7/03032 founded by the Polish National Science Centre.
