Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients.
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ABSTRACT:
SUBMITTER: Alobaid AS
PROVIDER: S-EPMC5328553 | biostudies-other | 2017 Mar
REPOSITORIES: biostudies-other
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Project description:Tedizolid is a novel oxazolidinone antimicrobial administered in its prodrug form, tedizolid phosphate, as a fixed once-daily dose. The pharmacokinetics of tedizolid has been studied in a relatively small proportion of morbidly obese (body mass index [BMI] of ?40 kg/m(2)) adults through population analyses with sparse sampling. The current study compared the intensively sampled plasma pharmacokinetics of tedizolid phosphate and tedizolid in 9 morbidly obese and 9 age-, sex-, and ideal body weight-matched nonobese (BMI, 18.5 to 29.9 kg/m(2)) healthy adult (18 to 50 years of age) volunteers after administration of a single intravenous dose of tedizolid phosphate. The median (range) weights were 72.6 kg (58.9 to 89.5 kg) and 117 kg (102 to 176 kg) for the mostly female (77.8%) nonobese and morbidly obese adults, respectively. Tedizolid phosphate concentrations were below the limit of quantitation in a majority of subjects after the 2-h time point. The tedizolid median (range) maximum concentration of drug in plasma (Cmax) and area under the concentration-time curve from 0 h to infinity (AUC0-?) were 2.38 (1.28 to 3.99) mg/liter and 26.3 (18.4 to 43.2) h · mg/liter, respectively, for morbidly obese subjects, and these were nonsignificantly different (P ? 0.214) from the values for nonobese subjects. Similarly, the volumes of distribution (Vz) (P = 0.110) and clearance (CL) values (P = 0.214) were comparable between groups. Nearly identical (P = 0.953) median tedizolid half-lives of approximately 12 h were observed for both groups. Tedizolid Vz and CL scaled with body weight, but not proportionately. The small and nonsignificant differences in tedizolid AUC0-? values between morbidly obese and nonobese subjects suggest that dose modification is not necessary for morbidly obese adults. (This study has been registered at ClinicalTrials.gov under number NCT02342418.).
| S-EPMC4958168 | biostudies-literature
Project description:Background and objectivesAlthough the pharmacokinetics of dexmedetomidine in healthy volunteers have been studied, there are limited data about the pharmacokinetics of long-term administration of dexmedetomidine in critically ill patients.MethodsThis population pharmacokinetic analysis was performed to quantify the pharmacokinetics of dexmedetomidine in critically ill patients following infusions up to 14 days in duration. The data consisted of three phase III studies (527 patients with sparse blood sampling, for a total of 2,144 samples). Covariates were included in a full random-effects covariate model and the most important covariate relationships were tested separately. The linearity of dexmedetomidine clearance was evaluated by observing steady-state plasma concentrations acquired at various infusion rates.ResultsThe data were adequately described with a one-compartment model. The clearance of dexmedetomidine was 39 (95 % CI 37-41) L/h and volume of distribution 104 (95 % CI 93-115) L. Both clearance and volume of distribution were highly variable between patients (coefficients of variation of 62 and 57 %, respectively), which highlights the importance of dose titration by response. Covariate analysis showed a strong correlation between body weight and clearance of dexmedetomidine. The clearance of dexmedetomidine was constant in the dose range 0.2-1.4 μg/kg/h.ConclusionsThe pharmacokinetics of dexmedetomidine are dose-proportional in prolonged infusions when dosing rates of 0.2-1.4 μg/kg/h, recommended by the Dexdor(®) summary of product characteristics, are used.
| S-EPMC3717151 | biostudies-literature
Project description:Predicting whether an obese critically ill patient can be successfully extubated may be specially challenging. Several weaning tests have been described but no physiological study has evaluated the weaning test that would best reflect the post-extubation inspiratory effort.This was a physiological randomized crossover study in a medical and surgical single-center Intensive Care Unit, in patients with body mass index (BMI) >35 kg/m2 who were mechanically ventilated for more than 24 h and underwent a weaning test. After randomization, 17 patients were explored using five settings : pressure support ventilation (PSV) 7 and positive end-expiratory pressure (PEEP) 7 cmH2O; PSV 0 and PEEP 7cmH2O; PSV 7 and PEEP 0 cmH2O; PSV 0 and PEEP 0 cmH2O; and a T piece, and after extubation. To further minimize interaction between each setting, a period of baseline ventilation was performed between each step of the study. We hypothesized that the post-extubation work of breathing (WOB) would be similar to the T-tube WOB.Respiratory variables and esophageal and gastric pressure were recorded. Inspiratory muscle effort was calculated as the esophageal and trans-diaphragmatic pressure time products and WOB. Sixteen obese patients (BMI 44 kg/m2?±?8) were included and successfully extubated. Post-extubation inspiratory effort, calculated by WOB, was 1.56 J/L?±?0.50, not statistically different from the T piece (1.57 J/L?±?0.56) or PSV 0 and PEEP 0 cmH2O (1.58 J/L?±?0.57), whatever the index of inspiratory effort. The three tests that maintained pressure support statistically underestimated post-extubation inspiratory effort (WOB 0.69 J/L?±?0.31, 1.15 J/L?±?0.39 and 1.09 J/L?±?0.49, respectively, p?<?0.001). Respiratory mechanics and arterial blood gases did not differ between the five tests and the post-extubation condition.In obese patients, inspiratory effort measured during weaning tests with either a T-piece or a PSV 0 and PEEP 0 was not different to post-extubation inspiratory effort. In contrast, weaning tests with positive pressure overestimated post-extubation inspiratory effort.Clinical trial.gov (reference NCT01616901 ), 2012, June 4th.
| S-EPMC5081985 | biostudies-literature
Project description:To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock.Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling.The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h(-1) (49%), a mean half-life of 9.6 h (range 0.83-28.6 h) and a total volume of distribution of 19.5 l (range 6.48-35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low.Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (>1 mg l(-1)).
| S-EPMC3243010 | biostudies-literature
Project description:This study investigates the optimal meropenem (MEM) dosing regimen for critically ill pediatric patients, for which there is a lack of pharmacokinetic (PK) studies. We conducted a retrospective single-center PK and pharmacodynamic (PD) analysis of 34 pediatric intensive care unit patients who received MEM. Individual PK parameters were determined by a two-compartment analysis. The median (range) age and body weight were 1.4 (0.03 to 14.6) years and 8.9 (2.7 to 40.9) kg, respectively, and eight (23.5%) patients received continuous renal replacement therapy (CRRT), three of whom received extracorporeal membrane oxygenation. Renal function, the systemic inflammatory response syndrome (SIRS) score for the clearance (CL), and the use of CRRT for the central volume of distribution (Vc) were identified as significant covariates. The mean CL, Vc, and peripheral volume of distribution (Vp) were 0.45 liters/kg/h, 0.49 liters/kg, and 0.34 liters/kg, respectively. The mean population CL of MEM increased by 35% in patients with SIRS and Vc increased by 66% in patients on CRRT in the final model. Dosing simulations suggested that the standard dosing regimen provided insufficient PD exposures of a 100% free time above the MIC, and higher doses (40 to 80 mg/kg of body weight/dose every 8 h) with a prolonged 3-h infusion were required to ensure the appropriate PD exposures for patients with SIRS. Our PK model indicated that critically ill pediatric patients are at risk of subtherapeutic exposure under the standard dosing regimen of MEM. A larger, prospective investigation confirming the safety and efficacy of higher concentrations and prolonged infusion of MEM is necessary.
| S-EPMC7848983 | biostudies-literature
Project description:PurposeTo develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective regimens.MethodsNon-linear mixed-effects modelling was used for the model development and covariate analysis. Target attainment of an ƒAUC0-24/MIC ≥ 100 for different MICs was calculated for standard dosing regimens. Monte Carlo simulations were performed to define the probability of target attainment (PTA) of several dosing regimens.ResultsA total of 204 blood samples were collected from 42 ICU patients treated with ciprofloxacin 400-1200 mg/day, with median values for age of 66 years, APACHE II score of 22, BMI of 26 kg/m2, and eGFR of 58.5 mL/min/1.73 m2. The median ƒAUC0-24 and ƒCmax were 29.9 mg•h/L and 3.1 mg/L, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model. We did not find any significant covariate to add to the structural model. The proportion of patients achieving the target ƒAUC0-24/MIC ≥ 100 were 61.9% and 16.7% with MICs of 0.25 and 0.5 mg/L, respectively. Results of the PTA simulations suggest that a dose of ≥ 1200 mg/day is needed to achieve sufficient ƒAUC0-24/MIC ratios.ConclusionsThe model described the pharmacokinetics of ciprofloxacin in ICU patients adequately. No significant covariates were found and high inter-individual variability of ciprofloxacin pharmacokinetics in ICU patients was observed. The poor target attainment supports the use of higher doses such as 1200 mg/day in critically ill patients, while the variability of inter-individual pharmacokinetics parameters emphasizes the need for therapeutic drug monitoring to ensure optimal exposure.
| S-EPMC7306030 | biostudies-literature
Project description:To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations.Prospective cohort study.Medical and surgical ICUs in a large tertiary care hospital in the United States.Patients with acute respiratory failure and/or shock who received fentanyl during the first 5 days of their ICU stay.We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to 5 days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 ?g/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found that fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92?kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance, intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35?L/hr (95% CI, 32-39?L/hr), 55?L/hr (95% CI, 42-68?L/hr), 203?L (95% CI, 140-266?L), and 523?L (95% CI, 428-618?L), respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart diseases were included.In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients.
| S-EPMC4755937 | biostudies-literature
Project description:Extracorporeal membrane oxygenation (ECMO) is associated with pharmacokinetic (PK) changes of drugs. It presents considerable challenges to providing optimal dosing regimens for patients receiving ECMO. We aimed to describe the population PK of remifentanil in critically ill adult patients receiving venoartrial extracorporeal membrane oxygenation (VA-ECMO) and to identify determinants associated with altered remifentanil concentrations. The population PK model of remifentanil was developed using nonlinear mixed effects modelling (NONMEM). Fifteen adult patients who received a continuous infusion of remifentanil during VA-ECMO participated in the study. The PK of remifentanil was best described by a one-compartment model with additive and proportional residual errors. Remifentanil concentrations were affected by sex and ECMO pump speed. The final PK model included the effect of sex and ECMO pump speed on clearance is developed as followed: clearance (L/h)?=?366?×?0.502sex?×?(ECMO pump speed/2350)2.04 and volume (L)?=?41. Remifentanil volume and clearance were increased in adult patients on VA-ECMO compared with previously reported patients not on ECMO. We suggest that clinicians should consider an increased remifentanil dosing to achieve the desired level of sedation and provide a dosing regimen according to sex and ECMO pump speed.
| S-EPMC5701170 | biostudies-literature
Project description:Background/aimIncreased body mass index (BMI) and neck circumference are the two independent predictors of difficult intubation. McGrath MAC X-Blade is a videolaryngoscope specifically designed for difficult intubations.Materials and methodsEighty patients with the American Society of Anesthesiologists (ASA) physical status I–III undergoing elective surgery requiring endotracheal intubation were enrolled in the study. Patients were divided into two groups, nonobese (BMI < 30) and morbidly obese (BMI > 35). All patients were intubated with the McGrath MAC X-Blade in both groups. View optimization and tube insertion maneuvers such as reinsertion of the device, slight removal of the device, cricoid pressure, handling force, 90° anticlockwise rotation of the tube, use of stylet, and head flexion maneuvers were recorded. Cormack–Lehane grades, insertion times, intubation, and total intubation times were recorded. The hemodynamic changes and postoperative minor complications were also recorded.ResultsBody mass index, neck circumference, Mallampati scores, and ASA physical status were statistically higher in the morbidly obese group (P < 0.001 and P < 0.05). Sternomental distances were shorter in the morbidly obese (P < 0.05). Cormack–Lehane grades were comparable among the groups. The morbidly obese patients required more reinsertion attempts and cricoid pressure maneuvers during intubation than the nonobese patients (P = 0.019 versus P = 0.012, respectively). Slight removal of the device, handling force, use of the stylet, 90° anticlockwise rotation of the tube, and head flexion maneuvers were also helpful in both groups. Although device insertion times were similar between the groups, intubation and total intubation times were longer in the morbidly obese group (P = 0.009 and P = 0.034, respectively). The groups were comparable in hemodynamic changes and postoperative minor complications.ConclusionThe McGrath MAC X-Blade videolaryngoscope could safely be used both in nonobese (BMI < 30) and morbidly obese (BMI > 35) patients with the aid of some key maneuvers and with a statistically significant but clinically negligible prolongation of the intubation time.
| S-EPMC7018374 | biostudies-literature
Project description:Background: Presently, colistin is commercially available in two different forms, namely, colistin sulfate and its sulphomethylated derivative, colistimethate sodium (CMS). However, in the currently reported studies, most of the clinical studies on colistin for parenteral use are referred to as CMS. Data on the pharmacokinetics (PK), clinical efficacy, and side effects of colistin sulfate in clinical use have not been reported. Methods: This retrospective study was performed on carbapenem-resistant organism (CRO)-infected patients treated with colistin sulfate for more than 72 h. The population pharmacokinetic model was developed using the NONMEM program. The clinical outcomes including clinical treatment efficacy, microbiological eradication, and nephrotoxicity were assessed. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients with normal or decreased renal function. Results: A total of 42 patients were enrolled, of which 25 (59.52%) patients were considered clinical treatment success and 29 (69.06%) patients had successful bacteria elimination at the end of treatment. Remarkably, no patient developed colistin sulfate-related nephrotoxicity. A total of 112 colistin concentrations with a range of 0.28-6.20 mg/L were included for PK modeling. The PK characteristic of colistin was well illustrated by a one-compartment model with linear elimination, and creatinine clearance (CrCL) was identified as a covariate on the clearance of colistin sulfate that significantly explained inter-individual variability. Monte Carlo simulations showed that the recommended dose regimen of colistin sulfate, according to the label sheet, of a daily dose of 1-1.5 million IU/day, given in 2-3 doses, could attain PTA > 90% for MICs ≤ 0.5 μg/mL, and that a daily dose of 1 million IU/day could pose a risk of subtherapeutic exposure for MIC ≥1 μg/ml in renal healthy patients. Conclusion: Renal function significantly affects the clearance of colistin sulfate. A dose of 750,000 U every 12 h was recommended for pathogens with MIC ≤1 μg/ml. The dosage recommended by the label inserts had a risk of subtherapeutic exposure for pathogens with MIC ≥2 μg/ml. Despite higher exposure to colistin in patients with acute renal insufficiency, dose reduction was not recommended.
| S-EPMC9243584 | biostudies-literature