Dexmedetomidine metabolic clearance is not affected by fat mass in obese patients

Rolle, Augusto; Paredes, Sílvia; Cortínez, Luis Ignacio; Anderson, Brian J.; Quezada, Nicolás; Solari, Sandra; Allende, F.; Torres, Javiera; Cabrera, Daniel; Contreras, Víctor; Carmona, J.; Ramírez, Carolina; Oliveros, Ana Lucia; Ibacache, Mauricio

doi:10.1016/j.bja.2018.01.040

Cited by 28 publications

(24 citation statements)

References 42 publications

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“…In addition, they also showed that for any lean body mass, total CL decreased associated with major fat mass. In a second trial by the same study group, authors confirmed that lean body mass was an appropriate dosing scalar for size in obese patients and showed that decreased hepatic blood had a significant effect on the CL of DEX (Rolle et al, 2018). The observed CL reduction in this population is most probably explained by a relative overdose of obese patients caused by TBW-based dosing schemes.…”

Section: Pharmacokinetic Propertiesmentioning

confidence: 86%

See 1 more Smart Citation

Dexmedetomidine Improves Cardiovascular and Ventilatory Outcomes in Critically Ill Patients: Basic and Clinical Approaches

et al. 2020

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Dexmedetomidine (DEX) is a highly selective a2-adrenergic agonist with sedative and analgesic properties, with minimal respiratory effects. It is used as a sedative in the intensive care unit and the operating room. The opioid-sparing effect and the absence of respiratory effects make dexmedetomidine an attractive adjuvant drug for anesthesia in obese patients who are at an increased risk for postoperative respiratory complications. The pharmacodynamic effects on the cardiovascular system are known; however the mechanisms that induce cardioprotection are still under study. Regarding the pharmacokinetics properties, this drug is extensively metabolized in the liver by the uridine diphosphate glucuronosyltransferases. It has a relatively high hepatic extraction ratio, and therefore, its metabolism is dependent on liver blood flow. This review shows, from a basic clinical approach, the evidence supporting the use of dexmedetomidine in different settings, from its use in animal models of ischemia-reperfusion, and cardioprotective signaling pathways. In addition, pharmacokinetics and pharmacodynamics studies in obese subjects and the management of patients subjected to mechanical ventilation are described. Moreover, the clinical efficacy of delirium incidence in patients with indication of non-invasive ventilation is shown. Finally, the available evidence from DEX is described by a group of Chilean pharmacologists and clinicians who have worked for more than 10 years on DEX.

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Section: Pharmacokinetic Propertiesmentioning

confidence: 86%

“…The observed CL reduction in this population is most probably explained by a relative overdose of obese patients caused by TBW-based dosing schemes. In this setting, scaling doses to FFM or allometric TBW seems more relevant (Cortinez et al, 2015;Hannivoort et al, 2015;Rolle et al, 2018).…”

Section: Pharmacokinetic Propertiesmentioning

confidence: 99%

Dexmedetomidine Improves Cardiovascular and Ventilatory Outcomes in Critically Ill Patients: Basic and Clinical Approaches

et al. 2020

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“…The liveralong with the kidney-plays a central role in the clearance of peripheral circulating amyloid beta through metabolic detoxification. In the state of hepatic inflammation and especially in more advanced stages like cirrhosis, amyloid beta uptake into hepatocytes and consequently excretion into the bile may be impaired leading to higher amyloid beta levels in the circulation [22,[24][25][26]. A recent genetic analysis performing network clustering analyses found 189 shared genes between NAFLD and Alzheimer's disease and illustrated shared pathways between both diseases including long fatty acid metabolism, IL-17 signaling, and carbohydrate metabolism [27].…”

Section: Discussionmentioning

confidence: 99%

Incident Dementia in Elderly Patients with Nonalcoholic Fatty Liver Disease in Germany

Labenz

Kostev²,

Kaps

et al. 2020

Dig Dis Sci

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Dementia and NAFLD are two frequent conditions that share underlying risk factors mainly in the realm of metabolic disease. Additionally, an association between NAFLD and brain aging has been proposed. Therefore, we investigated the hypothesis if NAFLD is an independent risk factor for emerging dementia. In this population-based cohort study, elderly patients (≥ 65 years) with NAFLD diagnosed between 2000 and 2015 were matched 1:1 to a cohort without NAFLD based on ICD-10 coding in the Disease Analyzer database. Matching criteria were age, sex, physician, index year, and co-diagnoses associated with dementia. The primary outcomes of this study were all-cause dementia diagnoses, the incidence of vascular dementia, and antidementive drug prescription. A total of 22,317 patients with NAFLD were matched to 22,317 patients without NAFLD. Within 10 years of the index date, 16.0% of patients with NAFLD and 15.6% of the patients without NAFLD were diagnosed with dementia. On Cox regression analysis, there is no association between NAFLD and the incidence of all-cause dementia (HR 0.97, 95% CI 0.92-1.04), vascular dementia (HR 0.89, 95% CI 0.78-1.02), or the new prescription of antidementive therapy (HR 0.87, 95% CI 0.76-1.01). In sensitivity analyses, there was no association between NAFLD and dementia in different age-groups as well as men or women. In conclusion, in this database study of elderly patients coded with NAFLD no independent association with incident dementia was detected. Risk assessment regarding dementia in patients with NAFLD should be carried out in the same way as for metabolic burdened patients.

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“…In this model, all structural parameters were allometrically scaled using a fixed exponent of 0.75 on clearance parameters (CL, Q) and 1 on volumes of distribution (V 1 , V 2 ) (Eqs. [1][2][3][4]. A sigmoidal function was used to describe maturation of clearance, including a maturation half-life (TM 50 ) which represents the postmenstrual age (PMA) at which maturation has reached 50% of the adult value, and an exponent (Hill factor, N) describing the steepness of the maturation curve (Eq.…”

Section: Initial Dose Selectionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Dijkman

Cock

Smets

et al. 2019

Eur J Clin Pharmacol

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Purpose There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. Methods A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a firstin-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. Results Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. Conclusions The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population.

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Dexmedetomidine metabolic clearance is not affected by fat mass in obese patients

Abstract: NCT02557867.

Cited by 28 publications

References 42 publications

Dexmedetomidine Improves Cardiovascular and Ventilatory Outcomes in Critically Ill Patients: Basic and Clinical Approaches

Dexmedetomidine Improves Cardiovascular and Ventilatory Outcomes in Critically Ill Patients: Basic and Clinical Approaches

Incident Dementia in Elderly Patients with Nonalcoholic Fatty Liver Disease in Germany

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

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