Large inter-individual variability in pharmacokinetics of dexmedetomidine and its two major N-glucuronides in adult intensive care unit patients.

Dexmedetomidine (DMTD), an α2-adrenoceptor agonist, is commonly used for sedation and analgesia in intensive care unit (ICU) patients. The primary plasma metabolites of DMTD are its direct N-glucuronides, namely N3-glucuronide of dexmedetomidine (DG1) and N1-glucuronide of dexmedetomidine (DG2), accounting for 41% of DMTD metabolism in healthy volunteers. Since variations on the extent of N-glucuronidation could be one of the key factors contributing to the high interpatient differences of DMTD pharmacokinetics in ICU patients and its subsequent sedative effect. In order to fully evaluate the N-glucuronidation of DMTD in ICU patients, the current study aimed to develop a LC/MS/MS method to simultaneously quantify DMTD and its two major N-glucuronides, DG1 and DG2, in plasma samples and describe their pharmacokinetics in adult ICU patients. Solid-phase extraction cartridges were used to effectively extract DMTD, DG1 and DG2 from 0.4 mL plasma with the internal standard tolazoline. The method was applied in determining the pharmacokinetic profiles of DMTD, DG1, and DG2 in nine ICU patients (mean ±â€¯SD admission severity of illness APACHE II score 23 ±â€¯5) receiving dexmedetomidine infusion for 667 to 3518 min. Under the optimized LC/MS/MS conditions, no endogenous interference from blank plasma was observed. The linear range was 25-5000 pg/mL for DMTD, 50-5000 pg/mL for DG1, and 56-2800 pg/mL for DG2 with good linearity (r2 ranges: 0.997-0.999, 0.993-0.999, and 0.993-0.998 for DMTD, DG1 and DG2 respectively). The precision, accuracy and the stability of DMTD, DG1, and DG2 at their quality control concentrations complied with Food and Drug Administration bioanalytical criteria. The assay was applied in determining the pharmacokinetic profiles of DMTD, DG1, and DG2 in nine ICU patients. The range of AUCDG1/AUCDMTD (from 0.40 to 2.20) and AUCDG2/AUCDMTD (from 0.15 to 2.02) suggested large inter-patient differences in the glucuronidation of DMTD. The mean AUC0-∞ ratio between total glucuronides and DMTD in ICU patients receiving infusions (2.09, range 0.55-4.16) appeared lower than the reported value in healthy volunteers receiving bolus intravenous injection (2.86). This description of the pharmacokinetics of DMTD, DG1, and DG2 in ICU patients is novel and suggests that pathophysiological changes in critically ill patients may have potential to decrease the glucuronidation of DMTD.

Altered Pharmacokinetics in Prolonged Infusions of Sedatives and Analgesics Among Adult Critically Ill Patients: A Systematic Review.

PURPOSE: The pharmacokinetic (PK) parameters of many drugs are altered as a consequence of the pathophysiological changes associated with critical illness. The critically ill population presents challenges when titrating infusions of sedatives and analgesics to maintain optimal sedation and pain levels. This systematic review examined the PK data in critically ill adult patients with prolonged infusions (>24 hours) of commonly used sedatives and analgesics to highlight possible altered PK parameters compared with noncritically ill patients. METHODS: A literature search of PK studies was performed by using MEDLINE (1946-December 2017) and EMBASE (1910-December 2017); we identified further studies by citation tracking (Web of Science) and checked references of retrieved studies and review articles. All studies were included that were published in English, Chinese, or German; conducted in critically ill adult patients receiving lorazepam, midazolam, propofol, dexmedetomidine, sufentanil, alfentanil, remifentanil, morphine, or fentanyl infusion for ≥24 hours; and reported PK parameters. When appropriate, we conducted a meta-analysis on volume of distribution at steady state (Vdss) (liters), clearance (Cl) (liters per hour), and elimination t1/2 (hours) by using a DerSimonian-Laird random effects model to estimate the summary mean and 95% CIs. Results were compared with commonly reported PK ranges in 70-kg noncritically ill patients. FINDINGS: Thirty-three randomized controlled trials and prospective cohort studies were identified involving 1803 adult critically ill patients with 35 drug treatment arms: fifteen midazolam (n = 906) studies, three dexmedetomidine (n = 561), nine propofol (n = 165), four lorazepam (n = 86), one morphine (n = 20), two remifentanil (n = 55), and one sufentanil (n = 10). Each study showed large variations in Vdss, Cl, and elimination t1/2 within and between individual participants. High clinical and methodical heterogeneity between the dexmedetomidine studies prevented the direct comparison of PK parameters between critically ill and noncritically ill patients. Use of midazolam, propofol, and lorazepam in critically ill patients was associated with at least a 2- to 4-fold increase in Vdss compared with noncritically ill patients; Cl decreased ∼2-fold for midazolam and 10-fold for morphine. Critically ill patients receiving prolonged infusions of midazolam, propofol, remifentanil, and sufentanil had at least 2-fold longer elimination or terminal t1/2 than noncritically ill patients. IMPLICATIONS: These findings show a marked difference in many PK parameters from those reported for noncritically ill patients. Initiatives to improve the delivery of prolonged sedatives and analgesic infusions should be informed by PK parameters (Vdss, context-sensitive t1/2, and elimination t1/2) and data derived from critically ill patients.

Prolonged infusion of sedatives and analgesics in adult intensive care patients: A systematic review of pharmacokinetic data reporting and quality of evidence.

Although pharmacokinetic (PK) data for prolonged sedative and analgesic agents in intensive care unit (ICU) has been described, the number of publications in this important area appear relatively few, and PK data presented is not comprehensive. Known pathophysiological changes in critically ill patients result in altered drug PK when compared with non-critically ill patients. ClinPK Statement was recently developed to promote consistent reporting in PK studies, however, its applicability to ICU specific PK studies is unclear. In this systematic review, we assessed the overall ClinPK Statement compliance rate, determined the factors affecting compliance rate, graded the level of PK evidence and assessed the applicability of the ClinPK Statement to future ICU PK studies. Of the 33 included studies (n=2016), 22 (67%) were low evidence quality descriptive studies (Level 4). Included studies had a median compliance rate of 80% (IQR 66% to 86%) against the ClinPK Statement. Overall pooled compliance rate (78%, 95% CI 73% to 83%) was stable across time (P=0.38), with higher compliance rates found in studies fitting three compartments models (88%, P<0.01), two compartments models (83%, P<0.01) and one compartment models (77%, P=0.17) than studies fitting noncompartmental or unspecified models (69%) (P<0.01). Data unique to the interpretation of PK data in critically ill patients, such as illness severity (48%), organ dysfunction (36%) and renal replacement therapy use (32%), were infrequently reported. Discrepancy between the general compliance rate with ClinPK Statement and the under-reporting of ICU specific parameters suggests that the applicability of the ClinPK Statement to ICU PK studies may be limited in its current form.