scholarly journals P103 Target attainment of amikacin therapy in critically ill children

2019 ◽  
Vol 104 (6) ◽  
pp. e60.2-e61
Author(s):  
J Verbruggen ◽  
K Jakipbayeva ◽  
T Van Der Heggen ◽  
E Dhont ◽  
L Dhondt ◽  
...  
Keyword(s):  
Steady State ◽  
Pilot Study ◽  
Critically Ill ◽  
Critically Ill Children ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Dosing Regimen ◽  
Target Attainment ◽  
Clinical Pharmacokinetics

BackgroundResearch regarding the optimal amikacin (AMI) dosing regimen in critically ill children is scarce.1 Optimal AMI efficacy has been observed with plasma peak over minimal inhibitory concentration of the suspected pathogen (peak/MIC) ratios of 8 to 10. Plasma trough levels (Cmin) >5mcg/ml are related to its toxicity.The objectives of this pilot study were to: (1) evaluate target attainment rate and occurrence of supratherapeutic concentrations in early and assumed steady-state dose conditions, and (2) investigate the correlation between AMI clearance and estimated glomerular filtration (eGFR).MethodsChildren admitted to the ICU receiving intravenous AMI (20 mg/kg once daily) were included. Serial blood samples were obtained from early (1st/2nd) and assumed steady-state (SS) doses. The evaluated target peak concentration range was 54–64 mcg/ml, assuming a Pseudomonas aeruginosa infection with Eucast MIC breakpoint of 8 mg/L, and a Cmin threshold of 5 mcg/L. eGFR was estimated using the modified Schwartz formula. AMI clearance was calculated using noncompartmental PK analysis. Correlation was assessed by means of a scatter plot and Pearson Correlation Coefficient (r).ResultsTwenty-one patients (median age1,5 years; range:0,5 months-14 year, median eGFR 162 ml/min/1,73m2 (range:107–475 ml/min/1,73m2) were included. In early dose conditions, 69% of patients had therapeutic peak concentrations (median: 60 mcg/ml; range:26–73 mcg/ml). In SS conditions, 60% of patients had therapeutic peak concentrations (median: 59 mcg/ml; range:35–83 mcg/ml). Only one supratherapeutic Cmin was observed. AMI clearance (median 0.08L/h/kg; range: 0.05–0.91 L/h/kg) was comparable to what has been previously reported but showed no correlation with eGFR (r=0.1; p=0,66) [1].ConclusionThis pilot study suggest that the current AMI dosing regimen may lead to subtherapeutic concentrations in patients infected with less susceptible pathogens. Supratherapeutic Cmin were far less of a concern. Dose adjustments of renally cleared drugs based on eGFR may not be reliable in this patient population.ReferencesIllamola SM, Sherwin CM, van Hasselt JGC. Clinical Pharmacokinetics of Amikacin in Pediatric Patients: A Comprehensive review of Population Pharmacokinetic Analysis. Clin Pharmacokinet ( 2018) 57:1217.Disclosure(s)Nothing to disclose

scholarly journals Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by Gram-Negative Bacteria

2009 ◽  
Vol 53 (8) ◽  
pp. 3430-3436 ◽  
Author(s):  
D. Plachouras ◽  
M. Karvanen ◽  
L. E. Friberg ◽  
E. Papadomichelakis ◽  
A. Antoniadou ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Colistin Methanesulfonate

ABSTRACT Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

scholarly journals Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children

2015 ◽  
Vol 60 (1) ◽  
pp. 522-531 ◽  
Author(s):  
Kristen Nichols ◽  
Eun Kyoung Chung ◽  
Chad A. Knoderer ◽  
Lauren E. Buenger ◽  
Daniel P. Healy ◽  
...  
Keyword(s):  
Steady State ◽  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Study Objective ◽  
Population Pharmacokinetics And Pharmacodynamics ◽  
Extended Infusion

ABSTRACTThe study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m2, respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.

scholarly journals New Colistin Population Pharmacokinetic Data in Critically Ill Patients Suggesting an Alternative Loading Dose Rationale

2014 ◽  
Vol 58 (12) ◽  
pp. 7324-7330 ◽  
Author(s):  
N. Grégoire ◽  
O. Mimoz ◽  
B. Mégarbane ◽  
E. Comets ◽  
D. Chatelier ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Loading Dose ◽  
Liquid Chromatography Tandem Mass

ABSTRACTColistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

scholarly journals O33 Towards personalised weaning of sedatives and analgesics using mechanism-based modelling of iatrogenic withdrawal in critically ill children

2019 ◽  
Vol 104 (6) ◽  
pp. e14.3-e15
Author(s):  
S Goulooze ◽  
E Krekels ◽  
M van Dijk ◽  
T Hankemeier ◽  
D Tibboel ◽  
...  
Keyword(s):  
Critically Ill ◽  
Rating Scale ◽  
Numerical Rating Scale ◽  
Statistical Significance ◽  
Prolonged Treatment ◽  
Morphine Dependence ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Over Time

BackgroundProlonged treatment with analgesics and sedatives can result in iatrogenic withdrawal syndrome (IWS) in children being weaned from these drugs.1Personalized weaning strategies might lower the incidence of IWS, but this requires a quantitative understanding of withdrawal over time in individual patients.MethodsData from 81 children (aged 1 month to 17 years) collected during an observational clinical study on IWS2 were used, including a total of 1782 withdrawal assessments performed by PICU nurses, on a numerical rating scale (NRSwithdrawal) from 0 (no withdrawal) to 10 (worst withdrawal possible). Population pharmacokinetic models from literature were used to generate concentration-time profiles in each patient of all key analgesics and sedatives: morphine, fentanyl, methadone, midazolam, lorazepam, propofol, esketamine and clonidine. A mechanism-based withdrawal model was developed using NONMEM 7.3 to quantify IWS over time. The final model was used to perform simulations in which different weaning strategies were compared.ResultsA novel mechanism-based withdrawal model structure was developed with a hypothetical compartment, which equilibrates with the central pharmacokinetic compartment, and which characterizes the development and disappearance of drug dependence over time. With this model and available data, withdrawal dynamics could be established with statistical significance for fentanyl (p< 10-6), morphine (p=0.043) and esketamine (p=0.002), and not for any of the other drugs. Compared with fentanyl, development and disappearance of esketamine and morphine dependence is slower.ConclusionsGiven the patient‘s use of fentanyl, morphine and esketamine, the developed model can dynamically predict IWS from these substances under different weaning strategies. The results show that the optimal strategy for weaning of drug dependent children depends on both the type of drug and the drug levels prior to weaning. In this study, there was insufficient information to characterise midazolam withdrawal dynamics, potentially because of slow midazolam weaning with insufficiently high NRSwithdrawal scores.ReferencesBest KM, Boullata JI, Curley MAQ. Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: A Systematic Review and Conceptual Model. Pediatr Crit Care Med ( 2015) 16(2): 175–183.Ista E, de Hoog M, Tibboel D, Duivenvoorden HJ, van Dijk M. Psychometric evaluation of the sophia observation withdrawal symptoms scale in critically ill children. Pediatr Crit Care Med ( 2013).14(8): 761–769.Disclosure(s)Nothing to disclose

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 of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen

2019 ◽  
Vol 74 (10) ◽  
pp. 2984-2993
Author(s):  
Anders Thorsted ◽  
Anders N Kristoffersson ◽  
Sabine F Maarbjerg ◽  
Henrik Schrøder ◽  
Mikala Wang ◽  
...  
Keyword(s):  
Body Weight ◽  
Continuous Infusion ◽  
Cancer Chemotherapy ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Target Attainment ◽  
Body Weights ◽  
Dosing Regimens ◽  
The Impact

Abstract Background The β-lactam antibiotic piperacillin (in combination with tazobactam) is commonly chosen for empirical treatment of suspected bacterial infections. However, pharmacokinetic variability among patient populations and across ages leads to uncertainty when selecting a dosing regimen to achieve an appropriate pharmacodynamic target. Objectives To guide dosing by establishing a population pharmacokinetic model for unbound piperacillin in febrile children receiving cancer chemotherapy, and to assess pharmacokinetic/pharmacodynamic target attainment (100% fT &gt; 1×MIC and 50% fT &gt; 4×MIC) and resultant exposure, across body weights. Methods Forty-three children admitted for 89 febrile episodes contributed 482 samples to the pharmacokinetic analysis. The typical doses required for target attainment were compared for various dosing regimens, in particular prolonged infusions, across MICs and body weights. Results A two-compartment model with inter-fever-episode variability in CL, and body weight included through allometry, described the data. A high CL of 15.4 L/h (70 kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fT &gt; 4×MIC was achieved for an MIC of 4.0 mg/L in a typical patient with extended infusions of 2–3 (q6h) or 3–4 (q8h) h, at or below the standard adult dose (75 and 100 mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fT &gt; 1×MIC due to the rapid piperacillin elimination. Conclusions The licensed dose for children with febrile neutropenia (80 mg/kg q6h as a 30 min infusion) performs poorly for attainment of fT&gt;MIC pharmacokinetic/pharmacodynamic targets. Given the population pharmacokinetic profile, feasible dosing regimens with reasonable exposure are continuous infusion (100% fT &gt; 1×MIC) or prolonged infusions (50% fT &gt; 4×MIC).

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).

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