Pharmacokinetics of dexmedetomidine during analgosedation in ICU patients

Abstract

Dexmedetomidine (DEX) is a fairly new alfa2-agonist which has been increasingly used in recent years for analgosedation, mostly because it offers a unique ability of providing both moderate level of sedation and analgesia without respiratory depression. Despite of many papers published, there are still only a few concerning the PK of the drug given as long-term infusion in ICU patients. The aim of this work was to characterize the population pharmacokinetics of dexmedetomidine and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in intensive care unit. This study was performed in the group of 17 males and 10 females patients with a median age of 59.5 years and median body weight of 75 kg. Blood samples for dexmedetomidine assay were collected from arterial catheter, during and after discontinuation of a standard infusion, that ranged from 24 to 102 h. The following covariates were examined to influence dexmedetomidine PK: age, sex, body weight, patients’ health status described by Sequential Organ Failure Assessment Score (SOFA), inotropes usage, and infusion duration. The dexmedetomidine PK was best described by a two-compartment model. The typical values of PK parameters were estimated as 27 L for the volume of the central compartment, 87.6 L for the volume of the peripheral compartment, 38.5 L/h (9.2 mL/min/kg for a 70 kg patient) for systemic clearance and 46.4 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 dexmedetomidine PK. This study does not provide sufficient evidence to support the individualization of dexmedetomidine dosing based on age, sex, body weight, SOFA, and infusion duration.Electronic supplementary materialThe online version of this article (10.1007/s10928-017-9564-7) contains supplementary material, which is available to authorized users.

Population Pharmacokinetic Model of Dexmedetomidine in a Heterogeneous Group of Patients

“…In the present study, a 2‐compartment model best described the data, which was consistent with other published studies on dexmedetomidine PK 3,9,34‐37 . The typical value of systemic clearance equaled 34.7 L/h, which was in the lower range of literature values (33.7–53.4 L/h) 3,9‐11,32,34‐36,38,39 This value was also slightly lower than values estimated for other ICU patients with continuous infusion lasting >24 hours (38.5, 39.7, 43, and 57 L/h) 10,35,37,38 .…”

“…The intercompartmental clearance equaled 40.8 L/h and was similar to literature values for ICU patients (39.7, 46.4 L/h) 38,35 . The volume of distribution at steady state (108.6 L) was consistent with the summary of product characteristics of Dexdor (90–151 L) and with values estimated in other studies (93‐132 L) 6,10,35,37 . Some differences in typical model parameters are inevitable and may result from the patient's clinical condition and between‐study differences in experimental designs.…”

“…The typical value of systemic clearance equaled 34.7 L/h, which was in the lower range of literature values (33.7–53.4 L/h) 3,9‐11,32,34‐36,38,39 This value was also slightly lower than values estimated for other ICU patients with continuous infusion lasting >24 hours (38.5, 39.7, 43, and 57 L/h) 10,35,37,38 . The intercompartmental clearance equaled 40.8 L/h and was similar to literature values for ICU patients (39.7, 46.4 L/h) 38,35 . The volume of distribution at steady state (108.6 L) was consistent with the summary of product characteristics of Dexdor (90–151 L) and with values estimated in other studies (93‐132 L) 6,10,35,37 .…”

Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation

“…It is metabolised by glucuronidation and CYP2A6 hydroxylation and subsequently excreted in urine almost exclusively as metabolite [2]. Its pharmacokinetics has been described by a two-compartmental model both in adults [3][4][5][6][7] and children [8][9][10][11][12]. Still, other investigators have also reported the disposition of dexmedetomidine according to one-compartment [13] and three-compartment [14][15][16] models.…”

Dynamics of neurospecific enolase as a leading marker in determining the functional state of the blood-brain barrier in patients with metabolic coma

“…Враховуючи той факт, що зміни активності головного мозку тісно пов'язані з його метаболізмом, що без постійного інтенсивного надходження АТФ сповільнюється клітинний синтез, пригнічуються функції нейронів і, що для забезпечення енергетичних потреб головного мозку процес тканинного дихання, що потребує кисень, є більш ефективним, ніж гліколіз [13]. Важливим є своєчасне призначення патогенетично обґрунтованих речовин у складі інтенсивної терапії (ІТ), які б з першої хвилин впливали на провідний механізм втрати свідомості.…”