scholarly journals Dose Optimization of Cefpirome Based on Population Pharmacokinetics and Target Attainment during Extracorporeal Membrane Oxygenation

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Soyoung Kang ◽  
June Young Jang ◽  
Jongsung Hahn ◽  
Dasohm Kim ◽  
Jun Yeong Lee ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Population Pharmacokinetics ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Dose Optimization ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Target Attainment ◽  
Membrane Oxygenation ◽  
The Impact

ABSTRACT To obtain the optimal dosage regimen in patients receiving extracorporeal membrane oxygenation (ECMO), we developed a population pharmacokinetics model for cefpirome and performed pharmacodynamic analyses. This prospective study included 15 patients treated with cefpirome during ECMO. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF) at predose and 0.5 to 1, 2 to 3, 4 to 6, 8 to 10, and 12 h after cefpirome administration. The population pharmacokinetic model was developed using nonlinear mixed effects modeling and stepwise covariate modeling. Monte Carlo simulation was used to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) according to the MIC distribution. Cefpirome pharmacokinetics were best described by a two-compartment model. Covariate analysis indicated that serum creatinine concentration (SCr) was negatively correlated with clearance, and the presence of ECMO increased clearance and the central volume of distribution. The simulations showed that patients with low SCr during ECMO-ON had lower PTA than patients with high SCr during ECMO-OFF; so, a higher dosage of cefpirome was required. Cefpirome of 2 g every 8 h for intravenous bolus injection or 2 g every 12 h for extended infusion over 4 h was recommended with normal kidney function receiving ECMO. We established a population pharmacokinetic model for cefpirome in patients with ECMO, and appropriate cefpirome dosage regimens were recommended. The impact of ECMO could be due to the change in patient status on consideration of the small population and uncertainty in covariate relationships. Dose optimization of cefpirome may improve treatment success and survival in patients receiving ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.)

scholarly journals Population Pharmacokinetics and Dosing Optimization of Linezolid in Pediatric Patients

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Si-Chan Li ◽  
Qi Ye ◽  
Hua Xu ◽  
Long Zhang ◽  
Yang Wang
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Pediatric Patients ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Nonparametric Bootstrap ◽  
Bootstrap Analysis ◽  
Final Model

ABSTRACT Linezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children has increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited. The aim of this study was to develop a population pharmacokinetic model for linezolid in children and optimize the dosing strategy in order to improve therapeutic efficacy. We performed a prospective pharmacokinetic study of pediatric patients aged 0 to 12 years. The population pharmacokinetic model was developed using the NONMEM program. Goodness-of-fit plots, nonparametric bootstrap analysis, normalized prediction distribution errors, and a visual predictive check were employed to evaluate the final model. The dosing regimen was optimized based on the final model. The pharmacokinetic data from 112 pediatric patients ages 0.03 to 11.9 years were analyzed. The pharmacokinetics could best be described by a one-compartment model with first-order elimination along with body weight and the estimated glomerular filtration rate as significant covariates. Simulations demonstrated that the currently approved dosage of 10 mg/kg of body weight every 8 h (q8h) would lead to a high risk of underdosing for children in the presence of bacteria with MICs of ≥2 mg/liter. To reach the pharmacokinetic target, an elevated dosage of 15 or 20 mg/kg q8h may be required for them. The population pharmacokinetics of linezolid were characterized in pediatric patients, and simulations provide an evidence-based approach for linezolid dosage individualization.

scholarly journals Population Pharmacokinetic Model and Pharmacokinetic Target Attainment of Micafungin in Intensive Care Unit Patients

2017 ◽  
Vol 56 (10) ◽  
pp. 1197-1206 ◽  
Author(s):  
Lisa C. Martial ◽  
Rob ter Heine ◽  
Jeroen A. Schouten ◽  
Nicole G. Hunfeld ◽  
Henk J. van Leeuwen ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Target Attainment

scholarly journals Optimization of Dosage Regimen of Meropenem in Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation: A Prospective Cohort Study

2021 ◽  
Author(s):  
Soyoung Kang ◽  
Seungwon Yang ◽  
Jongsung Hahn ◽  
June Young Jang ◽  
Kyoung Lok Min ◽  
...  
Keyword(s):  
Cohort Study ◽  
Dosage Regimen ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Optimal Dosage Regimen ◽  
Venoarterial Extracorporeal Membrane Oxygenation ◽  
Va Ecmo

Abstract BackgroundPatients receiving venoarterial extracorporeal membrane oxygenation (VA ECMO) therapy often require antibiotics to prevent and treat infections. Our objective was to determine an optimal dosage regimen of meropenem in patients receiving VA ECMO by developing a population pharmacokinetic model.MethodsThis was a prospective cohort study. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF). The population pharmacokinetic model was developed using nonlinear mixed-effects modelling. A Monte Carlo simulation was used (n=10,000) to assess the probability of target attainment.ResultsThirteen adult patients on ECMO receiving meropenem were included. Meropenem pharmacokinetics was best fitted by a two-compartment model. Covariate analysis indicated that continuous renal replacement therapy (CRRT) was negatively correlated with clearance (CL). The final pharmacokinetic model was: CL (L/h) = 3.79 × 0.44CRRT; where use of CRRT = 1, no CRRT = 0, central volume of distribution (L) = 2.4, peripheral volume of distribution (L) = 8.56, and intercompartmental clearance (L/h) = 21.3. According to the simulation results, 1–2 g q8h intravenous administration over 20 min was sufficient in patients without CRRT for both susceptible (minimum inhibitory concentration (MIC) = 2 mg/L) and resistant (MIC = 8 mg/L) pathogens, regardless of ECMO use (40% fT>MIC target). However, if more aggressive treatment is needed (100% fT>MIC target), dose increment or extended infusion is recommended.ConclusionsWe established a population pharmacokinetic model for meropenem in patients receiving VA ECMO and suggested an optimal dosage regimen. These results should improve treatment success and survival in VA ECMO patients. Clinicaltrials.gov registration # NCT02581280

Population Pharmacokinetics and Dose Optimization of Piperacillin/tazobactam in Critically Ill Patients During Extracorporeal Membrane Oxygenation (ECMO) and Weaned from ECMO

2021 ◽  
Author(s):  
Jongsung Hahn ◽  
Kyoung Lok Min ◽  
Soyoung Kang ◽  
Seungwon Yang ◽  
Byung Hak Jin ◽  
...  
Keyword(s):  
Critical Illness ◽  
Extracorporeal Membrane Oxygenation ◽  
Volume Overload ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Close Monitoring ◽  
Membrane Oxygenation ◽  
Extended Infusion

Abstract Background: Piperacillin/tazobactam is commonly used for empirical or directed treatment of infections during extracorporeal membrane oxygenation therapy (ECMO). Critical illness and extracorporeal circulation, such as ECMO and continuous renal replacement therapy may alter the pharmacokinetic parameters. We aimed to develop a population pharmacokinetic model of piperacillin/tazobactam in ECMO patients and investigate the optimal dosage regimen to achieve a pharmacodynamics target.Methods: This was a prospective observational study of 26 ECMO patients who received piperacillin/tazobactam. A population PK model was developed using non-linear mixed-effects models and simulations were performed to evaluate patient variables, MIC levels, and dosage regimens in relation to the probability of target attainment (PTA). The acceptable piperacillin PTA was set at ≥90% for 50%ƒT >16 mg/L.Results: A total of 244 samples were collected (163 during ECMO and 81 weaned from ECMO). Thirteen patients (50%) underwent continuous venovenous hemodiafiltration (CVVHDF). In a 2-compartment model, clearance increased by 10.1% when patients weaned from ECMO. Because patients on CVVHDF had a significant residual renal function, CVVHDF was found non-relevant to clearance. Instead, volume overload which was main cause of CVVHDF and membrane adsorption might contribute to the increased volume of distribution. Creatinine clearance (CrCL) calculated by Cockcroft-Gault equation had a significant impact on clearance. Simulation demonstrated that extended infusion should be considered in ECMO patients with CrCL >60 mL/min. Our proposed regimen was extended infusion of 2/0.25 g q8h, 2/0.25 g 6h, 3/0.375 g q 6h, and 4/0.5g q6h for CrCL ≤40, 40–60, 60–130, and >130 mL/min, respectively. Furthermore, even a higher dose would be required when patients did not receive CVVHDF after weaning from ECMO, which was 4/0.5g q6h for CrCL >110 mL/minConclusions: Piperacillin/tazobactam PK changes observed in ECMO patients were associated with critical illness rather than ECMO itself. A recent guideline dose may result in underexposure against P.aeruginosa when ECMO patients have CrCL > 110 mL/min; therefore, close monitoring of renal clearance is crucial in ECMO patients who received piperacillin/tazobactam regardless of CVVHDF use to provide effective treatment of infections and promote recovery. Overall, this study provides preliminary insights into the incremental effects of critical illness, ECMO and CVVHDF on piperacillin/tazobactam PK.Trial Registration: Clinicaltrials.gov NCT02581280, December 1st, 2014.

scholarly journals Population Pharmacokinetics and Pharmacodynamic Target Attainment of Vancomycin in Adults on Extracorporeal Membrane Oxygenation: A Prospective Cohort Study

2020 ◽  
Author(s):  
Younghee Jung ◽  
Dong-Hwan Lee ◽  
Hyoung Soo Kim
Keyword(s):  
Steady State ◽  
Extracorporeal Membrane Oxygenation ◽  
Population Pharmacokinetics ◽  
Total Daily Dose ◽  
Therapeutic Drug ◽  
Target Attainment ◽  
Mixed Effect ◽  
Point Distribution ◽  
Membrane Oxygenation ◽  
Population Pk

The aim of this study was to develop a population pharmacokinetics (PK) model for vancomycin and to evaluate its pharmacodynamic target attainment in adults on extracorporeal membrane oxygenation (ECMO). After a single 1,000 mg dose of vancomycin, samples were collected 9 times per patient prospectively. A population PK model was developed using a nonlinear mixed effect model. The probability of target attainment (PTA) of vancomycin was evaluated for various dosing strategies using Monte Carlo simulation. The ratio of the area under the vancomycin concentration-time curve at steady-state over 24 h to the minimum inhibitory concentration (AUC/MIC) was investigated by applying the vancomycin break point distribution of MICs for methicillin-resistant Staphylococcus aureus. A total of 22 adult patients with 194 concentration measurements were included. The population PK was best described by a three-compartment model with a proportional residual error model. Vancomycin clearance and steady state volume of distribution were 0.0542 L/h/kg (4.01 L/h) and 29.6 L (0.400 L/kg), respectively. If the treatment target was only AUC/MIC ≥400, a total daily dose of 3 to 4 g would be optimal (PTA ≥90%) for patients with normal renal function (estimated glomerular filtration rate [eGFR] = 60–120 mL/min/1.73 m2) when MIC was presumed to be 1 mg/L. However, AUC/MIC 400 to 600 was difficult to attain with any dosing strategy regardless of MIC and eGFR. Thus, it is hard to achieve efficacy and safety targets in patients on ECMO using the population dosing approach with Monte Carol simulations, and therapeutic drug monitoring should be implemented in these patients.

scholarly journals Impact of gender, albumin, and CYP2C19 polymorphisms on valproic acid in Chinese patients: a population pharmacokinetic model

2020 ◽  
Vol 48 (8) ◽  
pp. 030006052095228
Author(s):  
Jinlin Guo ◽  
Yayu Huo ◽  
Fang Li ◽  
Yuanping Li ◽  
Zhaojun Guo ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Chinese Patients ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Mixed Effect ◽  
First Order ◽  
The Impact

Objective This prospective study aimed to establish the valproic acid (VPA) population pharmacokinetic model in Chinese patients and realise personalised medication on the basis of population pharmacokinetics. Methods The patients’ clinical information and VPA plasma concentrations were collected from The General Hospital of Taiyuan Iron & Steel (Group) Corporation (TISCO). Nonlinear mixed-effect modelling was used to build the population pharmacokinetic model. To characterise the pharmacokinetic data, a one-compartment pharmacokinetic model with first-order absorption and elimination was used. The first-order conditional estimation with η-ε interaction was applied throughout the model-developing procedure. The absorption rate constant (Ka) was fixed at 2.38 hour−1, and the impact of covariates on clearance and apparent volume of distribution were also explored. Medical records of 60 inpatients were reviewed prospectively and the objective function value (OFV) of the base model and final model were 851.813 and 817.622, respectively. Results Gender was identified as the covariate that had a significant impact on the volume of distribution, and albumin and CYP2C19 genotypes influenced clearance. Conclusion Bootstrap and VPC indicated that a reliable model had been developed that was based on the simulation results, and a simple-to-use dosage regimen table was created to guide clinicians for VPA drug dosing.

scholarly journals Optimizing gentamicin dosing in different pediatric age groups using population pharmacokinetics and Monte Carlo simulation

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Ragia H. Ghoneim ◽  
Abrar K. Thabit ◽  
Manar O. Lashkar ◽  
Ahmed S. Ali
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Population Pharmacokinetics ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Concentration Data ◽  
Once Daily ◽  
Dosing Regimens ◽  
Gentamicin Concentration

Abstract Introduction The use of once daily dosing of aminoglycosides in pediatrics is increasing but studies on dose optimization targeting the pediatric population are limited. This study aimed to derive a population pharmacokinetic model of gentamicin and apply it to design optimal dosing regimens in pediatrics. Methods Population pharmacokinetics of gentamicin in pediatrics was described from a retrospective chart review of plasma gentamicin concentration data (peak/ trough levels) of pediatric patients (1 month − 12 years), admitted to non-critically ill pediatrics. Monte Carlo simulations were performed on the resulting pharmacokinetic model to assess the probability of achieving a Cmax/MIC target of 10 mg/L over a range of gentamicin MICs of 0.5–2 mg/L and once daily gentamicin dosing regimens. Results: A two-compartment model with additive residual error best described the model with weight incorporated as a significant covariate for both clearance and volume of distribution. Monte Carlo simulations demonstrated a good probability of target attainment even at a MIC of 2 mg/L, where neonates required doses of 6-7 mg/kg/day and older pediatrics required lower daily doses of 4–5 mg/kg/day while maintaining trough gentamicin concentration below the toxicity limit of 1 mg/L. Conclusion: Once daily dosing is a reasonable option in pediatrics that allows target attainment while maintaining trough gentamicin level below the limits of toxicity.

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