Population Pharmacokinetic Model to Optimize Cefotaxime Dosing Regimen in Critically Ill Children

2017 ◽  
Vol 57 (7) ◽  
pp. 867-875 ◽  
Author(s):  
Agathe Béranger ◽  
Mehdi Oualha ◽  
Saïk Urien ◽  
Mathieu Genuini ◽  
Sylvain Renolleau ◽  
...  
Keyword(s):  
Critically Ill ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Dosing Regimen

scholarly journals Population Pharmacokinetics and Dose Optimization of Ganciclovir in Critically Ill Children

2021 ◽  
Vol 11 ◽  
Author(s):  
SiChan Li ◽  
Chang Shu ◽  
SanLan Wu ◽  
Hua Xu ◽  
Yang Wang
Keyword(s):  
Critically Ill ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Visual Predictive Check ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Population Parameter ◽  
Nonparametric Bootstrap ◽  
Dosing Regimens

Objective: The present study aims to establish a population pharmacokinetic model of ganciclovir and optimize the dosing regimen in critically ill children suffering from cytomegalovirus related disease.Methods: A total of 104 children were included in the study. The population pharmacokinetic model was developed using the Phoenix NLME program. The final model was validated by diagnostic plots, nonparametric bootstrap, visual predictive check, and normalized prediction distribution errors. To further evaluate and optimize the dosing regimens, Monte Carlo simulations were performed. Moreover, the possible association between systemic exposure and hematological toxicity were also monitored in the assessment of adverse events.Results: The ganciclovir pharmacokinetics could be adequately described by a one-compartment model with first-order elimination along with body weight and estimated glomerular filtration rate as significant covariates. As showed in this study, the typical population parameter estimates of apparent volume of distribution and apparent clearance were 11.35 L and 5.23 L/h, respectively. Simulations indicated that the current regimen at a dosage of 10 mg/kg/d would result in subtherapeutic exposure, and elevated doses might be required to reach the target ganciclovir level. No significant association between neutropenia, the most frequent toxicity reported in our study (19.23%), and ganciclovir exposure was observed.Conclusion: A population pharmacokinetic model of intravenous ganciclovir for critically ill children with cytomegalovirus infection was successfully developed. Results showed that underdosing of ganciclovir was relatively common in critically ill pediatric patients, and model-based approaches should be applied in the optimizing of empiric dosing regimens.

scholarly journals Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 54 ◽  
Author(s):  
Amaia Soraluce ◽  
Helena Barrasa ◽  
Eduardo Asín-Prieto ◽  
Jose Ángel Sánchez-Izquierdo ◽  
Javier Maynar ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Standard Dose ◽  
Compartment Model ◽  
Antimicrobial Treatment ◽  
Population Pharmacokinetic ◽  
Renal Replacement Therapies ◽  
Continuous Renal Replacement Therapies

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

scholarly journals Influence of Mechanical Ventilation on the Pharmacokinetics of Vancomycin Administered by Continuous Infusion in Critically Ill Patients

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Susanna Edith Medellín-Garibay ◽  
Silvia Romano-Moreno ◽  
Pilar Tejedor-Prado ◽  
Noelia Rubio-Álvaro ◽  
Aida Rueda-Naharro ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Creatinine Clearance ◽  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Stochastic Simulations ◽  
Population Pharmacokinetic

ABSTRACT Pathophysiological changes involved in drug disposition in critically ill patients should be considered in order to optimize the dosing of vancomycin administered by continuous infusion, and certain strategies must be applied to reach therapeutic targets on the first day of treatment. The aim of this study was to develop a population pharmacokinetic model of vancomycin to determine clinical covariates, including mechanical ventilation, that influence the wide variability of this antimicrobial. Plasma vancomycin concentrations from 54 critically ill patients were analyzed simultaneously by a population pharmacokinetic approach. A nomogram for dosing recommendations was developed and was internally evaluated through stochastic simulations. The plasma vancomycin concentration-versus-time data were best described by a one-compartment open model with exponential interindividual variability associated with vancomycin clearance and the volume of distribution. Residual error followed a homoscedastic trend. Creatinine clearance and body weight significantly dropped the objective function value, showing their influence on vancomycin clearance and the volume of distribution, respectively. Characterization based on the presence of mechanical ventilation demonstrated a 20% decrease in vancomycin clearance. External validation (n = 18) was performed to evaluate the predictive ability of the model; median bias and precision values were 0.7 mg/liter (95% confidence interval [CI], −0.4, 1.7) and 5.9 mg/liter (95% CI, 5.4, 6.4), respectively. A population pharmacokinetic model was developed for the administration of vancomycin by continuous infusion to critically ill patients, demonstrating the influence of creatinine clearance and mechanical ventilation on vancomycin clearance, as well as the implications for targeting dosing rates to reach the therapeutic range (20 to 30 mg/liter).

scholarly journals Using Population Pharmacokinetics To Determine Gentamicin Dosing during Extended Daily Diafiltration in Critically Ill Patients with Acute Kidney Injury

2010 ◽  
Vol 54 (9) ◽  
pp. 3635-3640 ◽  
Author(s):  
Jason A. Roberts ◽  
Jonathan Field ◽  
Adam Visser ◽  
Rosemary Whitbread ◽  
Mandy Tallot ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Kidney Injury ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic

ABSTRACT The objective of the present prospective pharmacokinetic study was to describe the variability of plasma gentamicin concentrations in critically ill patients with acute kidney injury (AKI) necessitating extended daily diafiltration (EDD-f) using a population pharmacokinetic model and to subsequently perform Monte Carlo dosing simulations to determine which dose regimen achieves the pharmacodynamic targets the most consistently. We collected data from 28 gentamicin doses in 14 critically ill adult patients with AKI requiring EDD-f and therapeutic gentamicin. Serial plasma samples were collected. A population pharmacokinetic model was used to describe the pharmacokinetics of gentamicin and perform Monte Carlo simulations with doses of between 3 mg/kg of body weight and 7 mg/kg and at various time points before commencement of EDD-f to evaluate the optimal dosing regimen for achieving pharmacodynamic targets. A two-compartment pharmacokinetic model adequately described the gentamicin clearance while patients were on and off EDD-f. The plasma half-life of gentamicin during EDD-f was 13.8 h, whereas it was 153.4 h without EDD-f. Monte Carlo simulations suggest that dosing with 6 mg/kg every 48 h either 30 min or 1 h before the commencement of EDD-f results in 100% attainment of the target maximum concentration drug in plasma (<10 mg/liter) and sufficient attainment of the target area under the concentration-time curve from 0 to 24 h (AUC0-24; 70 to 120 mg·h/liter). None of the simulated dosing regimens satisfactorily achieved the targets of the minimum concentrations of drug in plasma (<1.0 mg/liter) at 24 h. In conclusion, dosing of gentamicin 30 min to 1 h before the commencement of an EDD-f treatment enables attainment of target peak concentrations for maximal therapeutic effect while enhancing drug clearance to minimize toxicity. Redosing in many patients should occur after 48 h, and we recommend the use of therapeutic drug monitoring to guide dosing to optimize achievement of the AUC0-24 targets.

scholarly journals Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Anne-Grete Märtson ◽  
Kim C. M. van der Elst ◽  
Anette Veringa ◽  
Jan G. Zijlstra ◽  
Albertus Beishuizen ◽  
...  
Keyword(s):  
Critically Ill ◽  
Rate Constant ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Content Type ◽  
The Mean

ABSTRACT The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for Candida glabrata, C. albicans, and C. parapsilosis, respectively. The final 2-compartment model included weight as a covariate on volume of distribution (V). The mean V of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant (Ke) was 0.09 (SD, 0.04) h−1, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h−1, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h−1. A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients.

scholarly journals Model-oriented Dose Optimization of Voriconazole in Critically Ill Children

2021 ◽  
Author(s):  
Jun Wang ◽  
Hua Xu ◽  
Ran Li ◽  
Sanlan Wu ◽  
Jili Zou ◽  
...  
Keyword(s):  
Body Weight ◽  
Critically Ill ◽  
Maintenance Dose ◽  
Maximum Velocity ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Final Model ◽  
Optimal Dosing ◽  
Dosing Regimens

Objective: This study aimed to employ a population pharmacokinetic (PK) model to optimize the dosing regimen of voriconazole (VRC) in children with a critical illness. Methods: A total of 99 children aged from 0.44 to 13.58 years old were included in this study. The stability and predictive performance of the final model were evaluated by statistical and graphical methods. The optimal dosing regimen was proposed for children with different body weight, CYP2C19 phenotype, and co-administration with omeprazole. Results: The PK of VRC was described by a two-compartment model with nonlinear Michaelis-Menten elimination. Body weight, CYP2C19 phenotype, and omeprazole were significant covariates on maximum velocity of elimination (V max ), which had an estimated typical value of 18.13 mg·h −1 . Bayesian estimation suggested that dose-normalized concentration and total exposure (C max /D, C min /D, AUC 24 /D) were significantly different between extensive metabolizers (EM) patients and poor metabolizer (PM) patients. To achieve the target concentration early, two loading doses of 9 mg·kg −1 q12h were reliable for most children, whereas three loading doses of 6-7.5 mg·kg −1 q8h were warranted for young children weighted ≤18kg (except PM patients). The maintenance doses decreased about 30-40% in PM patients than that in EM patients. For children aged < 2 years in EM, the maintenance dose could be as high as 9 mg·kg −1 . The maintenance dose of VRC was supposed to decrease slightly when co-administration with omeprazole. Conclusion: A population PK model of intravenous VRC for critically ill children has been successful developed. It is necessary to adjust dosing regimens according to CYP2C19 genotype. The optimal dosing regimens have been recommended basing on the final model.

scholarly journals Population Pharmacokinetics and Dosage Optimization of Linezolid in Critically Ill Pediatric Patients

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Mei Yang ◽  
Libo Zhao ◽  
Xiaohui Wang ◽  
Chen Sun ◽  
Hengmiao Gao ◽  
...  
Keyword(s):  
Body Weight ◽  
Critically Ill ◽  
Pediatric Patients ◽  
Pediatric Population ◽  
Treatment Success ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Dosing Regimen ◽  
Dosing Regimens

ABSTRACT Linezolid is an oxazolidinone antibiotic exhibiting efficacy against multidrug-resistant (MDR) Gram-positive-related infections. However, its population pharmacokinetic (PopPK) profile in critically ill Chinese children has not been characterized. Optimal dosing regimens should be established according to the population pharmacokinetic (PopPK)/pharmacodynamic (PD) properties of linezolid in the specific population. This work aims to describe the pharmacokinetic (PK) properties of linezolid, assess the factors affecting interpatient variability, and establish an optimized regimen for children in pediatric intensive care units (PICU). A single-center, prospective, open-labeled PK study was performed. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was applied to measure the plasma levels during linezolid treatment. PopPK analysis was conducted using Phoenix NLME software. A total of 63 critically ill pediatric patients were included. The data showed good fit for a two-compartment model with linear elimination. Body weight and aspartate aminotransferase (AST) were the most significant covariates explaining variabilities in linezolid PK for the pediatric population. The therapeutic target was defined as the ratio of the area under the drug plasma concentration-time curve over 24 h to a MIC (AUC/MIC) of >80. Different dosing regimens were evaluated using Monte Carlo simulation to determine the optimal dosage strategy for linezolid. Although the probability of target attainment (PTA) was high (>96%) for 10 mg/kg body weight every 8 h at a MIC of ≤1 mg/liter, it was lower than 70% at a MIC of >1 mg/liter. Thus, the dosing regimen required adjustment. When the dosing regimen was adjusted to 15 mg/kg every 6 h, the PTA increased from 63.6% to 94.6% at a MIC of 2 mg/liter, thereby indicating a higher degree of treatment success. Children with AST of >40 U/liter had a significantly higher AUC than those with AST of ≤40 U/liter (205.45 versus 159.96). Therefore, dosage adjustment was required according to the AST levels. The PopPK characteristics of linezolid in critically ill children were evaluated, and an optimal dosage regimen was constructed based on developmental PopPK/PD model and simulation. (This study has been registered in the Chinese Clinical Trial Registry under no. ChiCTR1900021386).

Sign in / Sign up

Export Citation Format

Share Document