The pharmacokinetics of prolonged infusions of dexmedetomidine in adult critically ill patients

Ph.D.Dexmedetomidine is an α₂-adrenoceptor agonist with analgesic sparing properties that is used for sedation and anxiolysis in the intensive care unit (ICU). Many critically ill patients have severe systemic illness resulting in pathophysiologic changes that can alter drug pharmacokinetics (PKs). There is a paucity of PK studies on prolonged infusions (>24h) of dexmedetomidine in critically ill patients.In the first study, the quantity and quality of data reporting in published PK studies conducted in critically ill patients was assessed against the ClinPK reporting guidelines to identify limitations in reporting pathophysiological factors specific to critically ill patients. In a systematic review of 6 parallel randomized controlled trials and 27 prospective cohort studies (n= 2016 critically ill adults), the overall compliance rate with ClinPK checklist was 78% (95% CI 73% to 83%). Severity of illness (48%), renal support used (32%) and organ failure (36%) were infrequently reported.For the second study, the systematic review was extended to identify PK differences between critically and non-critically ill patients receiving prolonged commonly used sedatives and analgesics. Key PK parameters (clearance [Cl], volume of distribution at steady state [Vdₛₛ] and elimination half-life [t₁/₂]) and covariates were extracted and analyzed from 34 studies (N= 1830 critically ill adults). Critically ill patients receiving prolonged infusion of midazolam showed a 2-fold higher Vdₛₛ, lower CL and 3-fold increase in elimination t1/2; propofol showed a 4-fold higher Vdss, similar CL and a longer terminal elimination t₁/₂. High clinical and methodology heterogeneity prevented direct comparisons of PK parameters of dexmedetomidine between critically ill and non-critically ill patients.The third study was to estimate the magnitude of dexmedetomidine protein binding in critically ill patients and assess its association with selected pathophysiological changes. Between September 2017 to March 2018, blood samples were taken from the start of dexmedetomidine infusion in 22 critically ill patients for dexmedetomidine protein binding fraction in plasma using generalized estimating equations and population non-linear mixed-effects PK modelling. The mean protein binding of 90.4% in our cohort was marginally lower (P=0.063) when compared to a healthy control (93.9%). In the last study, the study objective was to describe the PK profile of prolonged dexmedetomidine infusion in a critically ill cohort and compare the predictive accuracy of the population PK model developed with similar published PK models. The PK of dexmedetomidine in 22 critically ill patients was best described by a two-compartment model. Important critical illness-related covariates did not predict the magnitude of PK parameters. The pooled bias and inaccuracy of our model and 4 published model ranged from -0.98% to 11% and 23% to 31% respectively.In conclusion, although there was a paucity in the quantity and quality of PK data in critically ill patients receiving prolonged infusions of sedatives, PK parameters of several sedatives and analgesics were different from non-critically patients. Reduction in dexmedetomidine protein binding in critically ill patients was not clinically significant. Differences in the prediction performance between our model and other published models were not substantially large and clinical implications were therefore unclear.右美托咪定是一種具有鎮痛特性的α2-腎上腺素受體激動劑，可用於重症監護室（ICU）作為鎮靜和抗焦慮的藥物。許多危重患者患有嚴重的全身性疾病，導致病理生理變化，從而改變藥物的藥代動力學（PK）。關於重症患者使用右美托咪定的長時間輸注（> 24h）的藥代動力學研究比較貧乏。在第一項研究中，我們根據ClinPK 藥代動力學報告指引評估了在已發表重症患者中，進行的藥代動力學研究數據報告的數量和質量，以辨認出報告危重患者特有的病理生理因素的不足。在包含6 個平行隨機對照試驗，及27 個前瞻性隊列研究（包含 2016 名成年重症患者）的系統綜述文獻中，ClinPK 檢查表的總體依從率，為78％（95％信賴區間為 73％至83％）。而關於疾病嚴重程度（48％），使用血液透析（32％）和器官衰竭（36％）則不經常被披露。在第二項研究中的系統綜述，擴展到包含接受長時間輸注常用鎮靜劑和鎮痛藥的危重病人及非危重病人，之間的藥代動力學差異。我們從34 個已發表研究（包含 1830 名成年危重患者）中抽出並分析了關鍵藥代動力學參數（清除率[Cl]，穩態分佈容積[Vdss]和清除半衰期[t1 / 2]）和共變量。結果顯示接受咪達唑侖長輸注的危重患者，相對於非危重患者，顯示穩態分佈容積增加了2 倍，清除率下降，而清除半衰期增加了3 倍; 而接受異丙酚長輸注的危重患者，相對於非危重患者，顯示出高4 倍的穩態分佈容積，類似的清除率和更長的終末清除半衰期。右美托咪定的已發表研究中，由於有較高的臨床和研究執行方式的異質性， 所以危重患者和非危重患者之間藥代動力學參數不能夠被直接比較。第三項研究的目的是估計危重患者中，右美托咪定蛋白結合的程度，並評估與選定病理生理變化之間的關係。在2017 年9 月至2018 年3 月期間，我們使用了廣義估計方程和群體非線性混合效應藥代動力學建模，從22 名開始使用右美托咪定輸注的危重患者開始採集血液樣本，提取了右美托咪定蛋白質結合部分。在實驗危重患者群中平均蛋白結合率為90.4％，與健康對照組（93.9％）相比略低（P = 0.063）。最後一項研究的目的是描述在危重患者群中，接受長時間右美托咪定輸注的藥代動力學建模，並和類似已發表的藥代動力學模型預測準確性作出比較。 結果顯示22 名成年實驗危重患者群中的右美托咪定藥代動力學用兩室模型描述最為合適。危重病患相關的重要臨床共變量並未能夠預測關鍵的右美托咪定藥代動力學參數。我們的藥代動力學模型和4 個已發表藥代動力學模型的匯總偏差及不準確性，分別為-0.98％至11％和23％至31％。總結，儘管接受長期輸注鎮靜劑的危重患者，藥代動力學數據的數量和質量都比較缺乏，但成年危重患者在幾種鎮靜劑和鎮痛藥的藥代動力學參數上，與非危重患者是有所不同的。而在危重患者中右美托咪定蛋白結合程度的研究顯示出的右美托咪定蛋白結合的減少可能在臨床上沒有顯著意義。我們的藥代動力學模型與其他已發表模型之間，預測性能的差異並不大，因此臨床意義尚未清晰。Tse, Andrew Ho Wai.Thesis Ph.D. Chinese University of Hong Kong 2019.Includes bibliographical references (leaves 190-203).Abstracts also in Chinese.Title from PDF title page (viewed on 03, February, 2021)