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).

scholarly journals Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy

2018 ◽  
Vol 63 (2) ◽  
pp. e01957-18 ◽  
Author(s):  
Anne B. Leuppi-Taegtmeyer ◽  
Laurent Decosterd ◽  
Michael Osthoff ◽  
Nicolas J. Mueller ◽  
Thierry Buclin ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Normal Renal Function ◽  
Maintenance Dose ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Optimal Dosing ◽  
Colistimethate Sodium

ABSTRACT Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100 ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was <60 kg) with a consecutive 3-MU (respectively, 2 MU) maintenance dose at 8 h. CMS and colistin concentrations were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for, on average, 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady-state trough concentrations of at least 2.5 mg/liter were achieved in all patients receiving 3 MU at 8 h. In conclusion, a loading dose of 9 MU followed after 8 h by a maintenance dose of 3 MU every 8 h independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02081560.)

scholarly journals Population Pharmacokinetic Study of the Suitability of Standard Dosing Regimens of Amikacin in Critically Ill Patients with Open-Abdomen and Negative-Pressure Wound Therapy

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Cédric Carrié ◽  
Faustine Delzor ◽  
Stéphanie Roure ◽  
Vincent Dubuisson ◽  
Laurent Petit ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Body Weight ◽  
Monte Carlo Simulations ◽  
Critically Ill ◽  
Negative Pressure ◽  
Critically Ill Patients ◽  
Open Abdomen ◽  
Population Pharmacokinetic ◽  
Pressure Therapy ◽  
Dosing Regimens

ABSTRACT The aim was to assess the appropriateness of recommended regimens for empirical MIC coverage in critically ill patients with open-abdomen and negative-pressure therapy (OA/NPT). Over a 5-year period, every critically ill patient who received amikacin and who underwent therapeutic drug monitoring (TDM) while being treated by OA/NPT was retrospectively included. A population pharmacokinetic (PK) modeling was performed considering the effect of 10 covariates (age, sex, total body weight [TBW], adapted body weight [ABW], body surface area [BSA], modified sepsis-related organ failure assessment [SOFA] score, vasopressor use, creatinine clearance [CLCR], fluid balance, and amount of fluids collected by the NPT over the sampling day) in patients who underwent continuous renal replacement therapy (CRRT) or did not receive CRRT. Monte Carlo simulations were employed to determine the fractional target attainment (FTA) for the PK/pharmacodynamic [PD] targets (maximum concentration of drug [Cmax]/MIC ratio of ≥8 and a ratio of the area under the concentration-time curve from 0 to 24 h [AUC0–24]/MIC of ≥75). Seventy critically ill patients treated by OA/NPT (contributing 179 concentration values) were included. Amikacin PK concentrations were best described by a two-compartment model with linear elimination and proportional residual error, with CLCR and ABW as significant covariates for volume of distribution (V) and CLCR for CL. The reported V) in non-CRRT and CRRT patients was 35.8 and 40.2 liters, respectively. In Monte Carlo simulations, ABW-adjusted doses between 25 and 35 mg/kg were needed to reach an FTA of >85% for various renal functions. Despite an increased V and a wide interindividual variability, desirable PK/PD targets may be achieved using an ABW-based loading dose of 25 to 30 mg/kg. When less susceptible pathogens are targeted, higher dosing regimens are probably needed in patients with augmented renal clearance (ARC). Further studies are needed to assess the effect of OA/NPT on the PK parameters of antimicrobial agents.

ORGAN FAILURE AND C-REACTIVE PROTEIN BOTH AFFECT MIDAZOLAM CLEARANCE IN CRITICALLY ILL CHILDREN: A POPULATION PK MODEL

2015 ◽  
Vol 101 (1) ◽  
pp. e1.8-e1
Author(s):  
Nienke J Vet ◽  
Janneke M Brussee ◽  
Matthijs de Hoog ◽  
Miriam G Mooij ◽  
Carin WM Verlaat ◽  
...  
Keyword(s):  
Body Weight ◽  
Organ Failure ◽  
Critically Ill ◽  
Volume Of Distribution ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
C Reactive Protein ◽  
Population Pharmacokinetic Modeling ◽  
Reactive Protein ◽  
Organ Failures

ObjectivesTo study the effect of organ failure and inflammation on midazolam clearance in critically ill children, using population pharmacokinetic modeling.MethodsA total of 83 critically ill children (median age 5 months (range 1 day-17 years), n=523 samples) receiving intravenous midazolam for continuous sedation during mechanical ventilation were included. Disease severity was described using the validated and clinically used scores PELOD, PIM2 and PRISM II. Cytokines (IL-1, IL-2, IL-6, TNF-a) and C-reactive protein (CRP) were used as markers for inflammation. A population pharmacokinetic model for midazolam was developed using NONMEM 7.3. Body weight, age, severity of organ failure and inflammatory markers were considered as potential covariates.ResultsIn a two-compartmental PK model, body weight was found as most significant covariate for clearance and volume of distribution. Moreover, both severity of organ failure (PELOD) and inflammation (IL6 and CRP) were significant determinants of clearance (p<0.01), and either of these factors improved the model significantly. With increasing number of organ failures, midazolam clearance significantly reduced. CRP was linearly correlated with clearance (slope −0.095), with higher CRP levels resulting in lower clearances. Either one of the covariates could explain part of the variability in clearance.ConclusionFor midazolam clearance, apart from body weight, we found organ failure reflected by the PELOD score, and inflammation reflected by IL6 and CRP, as significant covariates. Most likely this effect is due to reduced activity of CYP3A in critically ill mechanically ventilated children. Both CRP concentration and organ failure should be considered when dosing midazolam and potentially other CYP3A substrates in critically ill children.

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 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 Population Pharmacokinetic Properties of Sulfadoxine and Pyrimethamine: a Pooled Analysis To Inform Optimal Dosing in African Children with Uncomplicated Malaria

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Miné de Kock ◽  
Joel Tarning ◽  
Lesley Workman ◽  
Elizabeth N. Allen ◽  
Mamadou M. Tekete ◽  
...  
Keyword(s):  
Body Weight ◽  
Young Children ◽  
Total Body Weight ◽  
Pooled Analysis ◽  
World Health ◽  
Population Pharmacokinetic ◽  
Z Score ◽  
Dosing Regimen ◽  
Optimal Dosing ◽  
Health Organization

ABSTRACT Sulfadoxine-pyrimethamine with amodiaquine is recommended by the World Health Organization as seasonal malaria chemoprevention for children aged 3 to 59 months in the sub-Sahel regions of Africa. Suboptimal dosing in children may lead to treatment failure and increased resistance. Pooled individual patient data from four previously published trials on the pharmacokinetics of sulfadoxine and pyrimethamine in 415 pediatric and 386 adult patients were analyzed using nonlinear mixed-effects modeling to evaluate the current dosing regimen and, if needed, to propose an optimized dosing regimen for children under 5 years of age. The population pharmacokinetics of sulfadoxine and pyrimethamine were both best described by a one-compartment disposition model with first-order absorption and elimination. Body weight, age, and nutritional status (measured as the weight-for-age Z-score) were found to be significant covariates. Allometric scaling with total body weight and the maturation of clearance in children by postgestational age improved the model fit. Underweight-for-age children were found to have 15.3% and 26.7% lower bioavailabilities of sulfadoxine and pyrimethamine, respectively, for each Z-score unit below −2. Under current dosing recommendations, simulation predicted that the median day 7 concentration was below the 25th percentile for a typical adult patient (50 kg) for sulfadoxine for patients in the weight bands of 8 to 9, 19 to 24, 46 to 49, and 74 to 79 kg and for pyrimethamine for patients in the weight bands of 8 to 9, 14 to 24, and 42 to 49 kg. An evidence-based dosing regimen was constructed that would achieve sulfadoxine and pyrimethamine exposures in young children and underweight-for-age young children that were similar to those currently seen in a typical adult.

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

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