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Population pharmacokinetic analysis of doripenem for Japanese patients in intensive care unit

ABSTRACT: We aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT). Twenty-one patients treated with DRPM (0.25 or 0.5 g) by intravenous infusion over 1 h were included in the study. Nine of the 21 patients were receiving CRRT. Plasma samples were obtained before and 1, 2, 4, 6 and 8 h after the first DRPM administration. PPK analysis was conducted by nonlinear mixed effects modeling using a two-compartment model. Total clearance (CLtotal) in the model was divided into CRRT clearance (CLCRRT) and body clearance (CLbody). The final model was: CLtotal (L h?1)?=?CLbody(non-CRRT)?=?3.65?×?(Ccr/62.25)0.64 in the absence of CRRT, or?=?CLbody(CRRT)?+?CLCRRT?=?2.49?×?(Ccr/52.75)0.42?+?CLCRRT in the presence of CRRT; CLCRRT?=?QE?×?0.919 (0.919 represents non-protein binding rate of DRPM); V1 (L)?=?10.04; V2 (L)?=?8.13; and Q (L h?1)?=?3.53. Using this model, CLtotal was lower and the distribution volumes (V1 and V2) tended to be higher compared to previous reports. Also, Ccr was selected as a significant covariate for CLbody. Furthermore, the contribution rate of CLCRRT to CLtotal was 30–40%, suggesting the importance of drug removal by CRRT. The population analysis model used in this study is a useful tool for planning DRPM regimen and administration. Our novel model may contribute greatly to proper use of DRPM in patients requiring intensive care.

SUBMITTER: Nonoshita K

PROVIDER: S-EPMC7747597 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVE:To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies. METHODS:Micafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations. RESULTS:A two-compartment model best fitted the data. Clearance was 1.10 (root square error 8%) L/h and V 1 and V 2 were 17.6 (root square error 14%) and 3.63 (root square error 8%) L, respectively. Median area under the concentration-time curve over 24 h (interquartile range) on day 14 for regimens I-V were 91 (67-122), 183 (135-244), 91 (67-122), 137 (101-183) and 183 (135-244) mg h/L, respectively, for a typical patient of 70 kg. For the MIC/area under the concentration-time curve >3000 target (all Candida spp.), PK target attainment was >91% on day 14 (MIC 0.016 mg/L epidemiological cut-off) for all of the dosing regimens but decreased to (I) 44%, (II) 91%, (III) 44%, (IV) 78% and (V) 91% for MIC 0.032 mg/L. For the MIC/area under the concentration-time curve >5000 target (non-C. parapsilosis spp.), PK target attainment varied between 62 and 96% on day 14 for MIC 0.016. CONCLUSIONS:The licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study.

Project description:BackgroundMany studies have compared quality of life of post-intensive care syndrome (PICS) patients with age-matched population-based controls. Many studies on PICS used the 36-item Short Form (SF-36) health survey questionnaire version 2, but lack the data for SF-36 values before and after intensive care unit (ICU) admission. Thus, clinically important changes in the parameters of SF-36 are unknown. Therefore, we determined the frequency of co-occurrence of PICS impairments at 6 months after ICU admission. We also evaluated the changes in SF-36 subscales and interpreted the patients' subjective significance of impairment.MethodsA prospective, multicenter, observational cohort study was conducted in 16 ICUs across 14 hospitals in Japan. Adult ICU patients expected to receive mechanical ventilation for > 48 h were enrolled, and their 6-month outcome was assessed using the questionnaires. PICS definition was based on the physical status, indicated by the change in SF-36 physical component score (PCS) ≥ 10 points; mental status, indicated by the change in SF-36 mental component score (MCS) ≥ 10 points; and cognitive function, indicated by the worsening of Short-Memory Questionnaire (SMQ) score and SMQ score at 6 months < 40. Multivariate logistic regression model was used to identify the factors associated with PICS occurrence. The patients' subjective significance of physical and mental symptoms was assessed using the 7-scale Global Assessment Rating to evaluate minimal clinically important difference (MCID).ResultsAmong 192 patients, 48 (25%) died at 6 months. Among the survivors at 6 months, 96 patients responded to the questionnaire; ≥ 1 PICS impairment occurred in 61 (63.5%) patients, and ≥ 2 occurred in 17 (17.8%) patients. Physical, mental, and cognitive impairments occurred in 32.3%, 14.6% and 37.5% patients, respectively. Population with only mandatory education was associated with PICS occurrence (odds ratio: 4.0, 95% CI 1.1-18.8, P = 0.029). The MCID of PCS and MCS scores was 6.5 and 8.0, respectively.ConclusionsAmong the survivors who received mechanical ventilation, 64% had PICS at 6 months; co-occurrence of PICS impairments occurred in 20%. PICS was associated with population with only mandatory education. Future studies elucidating the MCID of SF-36 scores among ICU patients and standardizing the PICS definition are required. Trial registration UMIN000034072.

Project description:Purpose: To determine whether inotrope administration is associated with increased all-cause mortality in cardiogenic shock (CS) patients and to identify inotropes superior for improving mortality. Methods: This retrospective cohort study analyzed data retrieved from the Philips Electronic ICU (eICU) database, a clinical database of 200,859 patients from over 208 hospitals located throughout the United States. The database was searched for patients admitted with CS to the intensive care unit (ICU) between 2014 and 2015. We evaluated 34,381 CS patients. They were classified into the inotrope and non-inotrope groups based on whether inotropes were administered during hospitalization. The primary endpoint was all-cause hospital mortality. Findings: In total, 15,021 (43.69%) patients received inotropes during hospitalization. The in-hospital mortality rate was significantly higher in the inotrope group than in the non-inotrope group (2,999 [24.03%] vs. 1,547 [12.40%], adjusted hazard ratio: 2.24; 95% confidence interval [CI]: 2.09-2.39; p < 0.0001). After propensity score matching according to the cardiac index, 359 patients were included in each group. The risk of ICU (OR 5.65, 95% CI, 3.17-10.08, p < 0.001) and hospital (OR 2.63, 95% CI: 1.75-3.95, p < 0.001) mortality in the inotrope group was significantly higher. In the inotrope group, the administration of norepinephrine ≤0.1 μg/kg/min and dopamine ≤15 μg/kg/min did not increase the risk of hospital mortality, and milrinone administration was associated with a lower mortality risk (odds ratio: 0.559, 95% CI: 0.430-0.727, p < 0.001). Meanwhile, the administration of >0.1 μg/kg/min dobutamine, epinephrine, and norepinephrine and dopamine >15 μg/kg/min was associated with a higher risk of hospital mortality. Conclusions: Inotropes should be used cautiously because they may be associated with a higher risk of mortality in CS patients. Low-dose norepinephrine and milrinone may associated with lower risk of hospital mortality in these patients, and supportive therapies should be considered when high-dose inotropes are administered.

Project description:Critically ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decrease quality of life of survivors. Acute Quadriplegic Myopathy (AQM) is one of the most common neuromuscular disorders associated with ICU-acquired muscle weakness. Although there are no available treatments for the ICU-acquired muscle weakness, it has been demonstrated that early mobilization can improve its prognosis and functional outcomes. This study aims at improving our understanding of the effects of passive mechanical loading on skeletal muscle structure and function by using a unique experimental rat ICU model allowing analyses of the temporal sequence of changes in mechanically ventilated and pharmacologically paralyzed animals at durations varying from 6 h to 14 days. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded vs. unloaded muscles after a 2-week ICU intervention. We demonstrated that the improved maintenance of muscle structure and function is likely a consequence of a reduced oxidative stress, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, ECM/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle structure and function associated with mechanical silencing in ICU patients, strongly supporting early and intense physical therapy in immobilized ICU patients. This study aims to unravel the effects of passive mechanical loading on skeletal muscle structure and function in an experimental rat ICU model at duration varying between 6h and 14 days. A total of 23 experimental female Sprague-Dawley rats were included in this study. The experimental rats were anaesthetized, treated with the neuromuscular blocking agent (NMBA) M-NM-1-cobrotoxin, mechanically ventilated and monitored for durations varying from 6h to 4 days (n=13), from 5 to 8 days (n=4), and from 9 to 14 days (n=6). The left leg of the animal was activated for 6 hours at the shortest duration and 12 hours per day at durations 12 hours and longer throughout the experiment, using a mechanical lever arm that produced a continuous passive maximal ankle joint flexions-extensions at a speed of 13.3 cycles per minute. Muscle biopsies were obtained from gastrocnemius muscle (proximal part) immediately after euthanasia, were quickly frozen in liquid propane cooled by liquid nitrogen, and stored at -80M-BM-0C. RNA was extracted.

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Population pharmacokinetic analysis of doripenem for Japanese patients in intensive care unit

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