Developmental population pharmacokinetics–pharmacodynamics and dosing optimization of cefoperazone in children

2020 ◽  
Vol 75 (7) ◽  
pp. 1917-1924
Author(s):  
Hai-Yan Shi ◽  
Kai Wang ◽  
Rong-Hua Wang ◽  
Yue-E Wu ◽  
Bo-Hao Tang ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Population Pharmacokinetics ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Open Label ◽  
Treatment Target ◽  
Two Compartment Model ◽  
Pharmacodynamic Analysis ◽  
Dosing Optimization

Abstract Objectives To evaluate the population pharmacokinetics of cefoperazone in children and establish an evidence-based dosing regimen using a developmental pharmacokinetic–pharmacodynamic approach in order to optimize cefoperazone treatment. Methods A model-based, open-label, opportunistic-sampling pharmacokinetic study was conducted in China. Blood samples from 99 cefoperazone-treated children were collected and quantified by HPLC/MS. NONMEM software was used for population pharmacokinetic–pharmacodynamic analysis. This study was registered at ClinicalTrials.gov (NCT03113344). Results A two-compartment model with first-order elimination agreed well with the experimental data. Covariate analysis showed that current body weight had a significant effect on the pharmacokinetics of cefoperazone. Monte Carlo simulation showed that for bacteria for which cefoperazone has an MIC of 0.5 mg/L, 78.1% of hypothetical children treated with ‘40 mg/kg/day, q8h, IV drip 3 h’ would reach the pharmacodynamic target. For bacteria for which cefoperazone has an MIC of 8 mg/L, 88.4% of hypothetical children treated with 80 mg/kg/day (continuous infusion) would reach the treatment goal. A 160 mg/kg/day (continuous infusion) regimen can cover bacteria for which cefoperazone has an MIC of 16 mg/L. Nevertheless, even if using the maximum reported dose of 160 mg/kg/day (continuous infusion), the ratio of hypothetical children reaching the treatment target was only 9.9% for bacteria for which cefoperazone has an MIC of 32 mg/L. Conclusions For cefoperazone, population pharmacokinetics were evaluated in children and an appropriate dosing regimen was developed based on developmental pharmacokinetics–pharmacodynamics. The dose indicated in the instructions (20–160 mg/kg/day) can basically cover the clinically common bacteria for which cefoperazone has an MIC of ≤16 mg/L. However, for bacteria for which the MIC is >16 mg/L, cefoperazone is not a preferred choice.

scholarly journals Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants

2019 ◽  
Vol 74 (8) ◽  
pp. 2128-2138 ◽  
Author(s):  
Evelyne Jacqz-Aigrain ◽  
Stéphanie Leroux ◽  
Alison H Thomson ◽  
Karel Allegaert ◽  
Edmund V Capparelli ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Intermittent Infusion ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Blue Book ◽  
Young Infants ◽  
Optimal Dosing ◽  
Two Compartment Model ◽  
Postmenstrual Age

Abstract Objectives In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. Methods A ‘meta-model’ with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0–24 of 400 mg·h/L at steady-state in at least 80% of neonates. Results A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0–24 target earlier than a standard ‘Blue Book’ dosage regimen in >89% of the treated patients. Conclusions The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.

scholarly journals Optimal Dosing of Ceftriaxone in Infants Based on a Developmental Population Pharmacokinetic-Pharmacodynamic Analysis

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Ya-Kun Wang ◽  
Yue-E Wu ◽  
Xue Li ◽  
Li-Yuan Tian ◽  
Muhammad Wasim Khan ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Sampling Strategy ◽  
Optimal Dose ◽  
Community Acquired Pneumonia ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Evidence Based ◽  
Open Label ◽  
Large Variability ◽  
Pharmacodynamic Analysis

ABSTRACT Ceftriaxone is a third-generation cephalosporin used to treat infants with community-acquired pneumonia. Currently, there is a large variability in the amount of ceftriaxone used for this purpose in this particular age group, and an evidence-based optimal dose is still unavailable. Therefore, we investigated the population pharmacokinetics of ceftriaxone in infants and performed a developmental pharmacokinetic-pharmacodynamic analysis to determine the optimal dose of ceftriaxone for the treatment of infants with community-acquired pneumonia. A prospective, open-label pharmacokinetic study of ceftriaxone was conducted in infants (between 1 month and 2 years of age), adopting an opportunistic sampling strategy to collect blood samples and applying high-performance liquid chromatography to quantify ceftriaxone concentrations. Developmental population pharmacokinetic-pharmacodynamic analysis was conducted using nonlinear mixed effects modeling (NONMEM) software. Sixty-six infants were included, and 169 samples were available for pharmacokinetic analysis. A one-compartment model with first-order elimination matched the data best. Covariate analysis elucidated that age and weight significantly affected ceftriaxone pharmacokinetics. According to the results of a Monte Carlo simulation, with a pharmacokinetic-pharmacodynamic target of a free drug concentration above the MIC during 70% of the dosing interval (70% fT>MIC), regimens of 20 mg/kg of body weight twice daily for infants under 1 year of age and 30 mg/kg twice daily for those older than 1 year of age were suggested. The population pharmacokinetics of ceftriaxone were established in infants, and evidence-based dosing regimens for community-acquired pneumonia were suggested based on developmental pharmacokinetics-pharmacodynamics.

scholarly journals Population Pharmacokinetics of Ciprofloxacin in Neonates and Young Infants Less than Three Months of Age

2014 ◽  
Vol 58 (11) ◽  
pp. 6572-6580 ◽  
Author(s):  
Wei Zhao ◽  
Helen Hill ◽  
Chantal Le Guellec ◽  
Tim Neal ◽  
Sarah Mahoney ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Newborn Infants ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Dosing Regimen ◽  
Creatinine Concentration ◽  
Young Infants

ABSTRACTCiprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.

scholarly journals Nemonoxacin Dosage Adjustment in Patients with Severe Renal Impairment Based on Population Pharmacokinetic and Pharmacodynamic Analysis

2021 ◽  
Author(s):  
Yi Li ◽  
Jianda Lu ◽  
Yue Kang ◽  
Xiaoyong Xu ◽  
Xin Li ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Compartment Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Healthy Controls ◽  
Dosing Regimen ◽  
Open Label ◽  
Optimal Dosing

Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic/pharmacodynamic (PPK/PD) analysis. Methods: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 48 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) against S. Pneumoniae and S. aureus was calculated by Monte Carlo simulation. Results: The data best fitted to a two-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L), and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4±6.5% in severe renal impairment patients and 66.1±16.8% in healthy controls. PPK/PD modeling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in severe renal impairment patients, evidenced by higher PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if MIC ≤ 0.5 mg/L. Conclusion: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

scholarly journals Body Surface Area-Based Dosing Regimen of Caspofungin in Children: a Population Pharmacokinetics Confirmatory Study

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Xin-Mei Yang ◽  
Stephanie Leroux ◽  
Thomas Storme ◽  
Dao-Lun Zhang ◽  
Tiphaine Adam de Beaumais ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Compartment Model ◽  
Dosing Regimen ◽  
Real World Data ◽  
Two Compartment Model ◽  
Pediatric Use ◽  
Best Fit

ABSTRACT We evaluated the population pharmacokinetics of caspofungin in children (2 to 12 years of age). The real-world data from 48 children were best fit by a two-compartment model with first-order elimination. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics, compared to body weight. The population pharmacokinetics of caspofungin confirmed that adjustment of caspofungin dosage based on body surface area is most appropriate for pediatric use.

scholarly journals Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Infants

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Zhong-Ren Shi ◽  
Xing-Kai Chen ◽  
Li-Yuan Tian ◽  
Ya-Kun Wang ◽  
Gu-Ying Zhang ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
High Performance ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Generation Cephalosporin ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Dosing Regimen ◽  
Age Range

ABSTRACT Ceftazidime, a third-generation cephalosporin, can be used for the treatment of adults and children with infections due to susceptible bacteria. To date, the pediatric pharmacokinetic data are limited in infants, and therefore we aimed to evaluate the population pharmacokinetics of ceftazidime in infants and to define the appropriate dose to optimize ceftazidime treatment. Blood samples were collected from children treated with ceftazidime, and concentrations of the drug were quantified by high-performance liquid chromatography with UV detection (HPLC-UV). A population pharmacokinetic analysis was performed using NONMEM software ( version 7.2.0). Fifty-one infants ( age range, 0.1 to 2.0 years ) were included. Sparse pharmacokinetic samples ( n = 90 ) were available for analysis. A one-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that body weight and creatinine clearance (CL CR ) were significant covariates influencing ceftazidime clearance. Monte Carlo simulation demonstrated that the currently used dosing regimen of 50 mg / kg twice daily was associated with a high risk of underdosing in infants. In order to reach the target of 70% of the time that the free antimicrobial drug concentration exceeds the MIC ( fT >MIC ), 25 mg/kg every 8 h (q8h) and 50 mg/kg q8h were required for MICs of 4 and 8 mg/liter, respectively. The population pharmacokinetic characteristics of ceftazidime were evaluated in infants. An evidence-based dosing regimen was established based on simulation.

scholarly journals O26 Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young Infants

2019 ◽  
Vol 104 (6) ◽  
pp. e11.2-e12
Author(s):  
E Jacqz-Aigrain ◽  
S Leroux ◽  
AH Thomson ◽  
K Allegaert ◽  
EV Capparelli ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Intermittent Infusion ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Blue Book ◽  
Young Infants ◽  
Optimal Dosing ◽  
Two Compartment Model ◽  
Current Weight

BackgroundIn the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.MethodsA ‘meta-model’ using NONMEM with 4894 concentrations from 1631 neonates was built and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming at reaching a target AUC0-24 of 400 mg*h/L at steady state in at least 80% of neonates.ResultsA two-compartment model best fitted the data. Current weight, post-menstrual age (PMA) and serum creatinine were the significant covariates for clearance (CL). After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg twice daily if < 35 weeks PMA and 15 mg/kg three times daily if ≥ 35 weeks PMA) achieved the AUC0-24 target earlier than a standard ‘Blue Book’ dosage regimen in more than 89% of the treated patients.ConclusionsThe results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and assist in the design of the model-based, multinational European trial, NeoVanc.Disclosure(s)Nothing to disclose

Population pharmacokinetics and dosing simulations of amoxicillin in obese adults receiving co-amoxiclav

2020 ◽  
Vol 75 (12) ◽  
pp. 3611-3618
Author(s):  
G Mellon ◽  
K Hammas ◽  
C Burdet ◽  
X Duval ◽  
C Carette ◽  
...  
Keyword(s):  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Open Label ◽  
Mixed Effect ◽  
Mean Values ◽  
Two Compartment Model ◽  
Amoxicillin Clavulanate ◽  
Dosing Regimens ◽  
Obese Subjects

Abstract Background Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav. Materials and methods Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC–tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix. Results Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT&gt;MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral). Conclusions Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.

scholarly journals Population Pharmacokinetics and Dosing Regimen Optimization of Meropenem in Cerebrospinal Fluid and Plasma in Patients with Meningitis after Neurosurgery

2016 ◽  
Vol 60 (11) ◽  
pp. 6619-6625 ◽  
Author(s):  
Cheng Lu ◽  
Yuyi Zhang ◽  
Mingyu Chen ◽  
Ping Zhong ◽  
Yuancheng Chen ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Population Pharmacokinetics ◽  
Compartment Model ◽  
Dosing Regimen ◽  
Target Attainment ◽  
Csf Drainage ◽  
Two Compartment Model ◽  
Dosing Regimens ◽  
Dosing Intervals ◽  
To Receive

ABSTRACTMeropenem is used to manage postneurosurgical meningitis, but its population pharmacokinetics (PPK) in plasma and cerebrospinal fluid (CSF) in this patient group are not well-known. Our aims were to (i) characterize meropenem PPK in plasma and CSF and (ii) recommend favorable dosing regimens in postneurosurgical meningitis patients. Eighty-two patients were enrolled to receive meropenem infusions of 2 g every 8 h (q8h), 1 g q8h, or 1 g q6h for at least 3 days. Serial blood and CSF samples were collected, and concentrations were determined and analyzed via population modeling. Probabilities of target attainment (PTA) were predicted via Monte Carlo simulations, using the target of unbound meropenem concentrations above the MICs for at least 40% of dosing intervals in plasma and at least of 50% or 100% of dosing intervals in CSF. A two-compartment model plus another CSF compartment best described the data. The central, intercentral/peripheral, and intercentral/CSF compartment clearances were 22.2 liters/h, 1.79 liters/h, and 0.01 liter/h, respectively. Distribution volumes of the central and peripheral compartments were 17.9 liters and 3.84 liters, respectively. The CSF compartment volume was fixed at 0.13 liter, with its clearance calculated by the observed drainage amount. The multiplier for the transfer from the central to the CSF compartment was 0.172. Simulation results show that the PTAs increase as infusion is prolonged and as the daily CSF drainage volume decreases. A 4-hour infusion of 2 g q8h with CSF drainage of less than 150 ml/day, which provides a PTA of >90% for MICs of ≤8 mg/liter in blood and of ≤0.5 mg/liter or 0.25 mg/liter in CSF, is recommended. (This study has been registered at ClinicalTrials.gov under identifier NCT02506686.)

POPULATION PHARMACOKINETICS AND DOSING OPTIMIZATION OF TEICOPLANIN IN CHILDREN WITH MALIGNANT HAEMATOLOGICAL DISEASE

2015 ◽  
Vol 101 (1) ◽  
pp. e1.41-e1
Author(s):  
Wei Zhao ◽  
Daolun Zhang ◽  
Thomas Storme ◽  
André Baruchel ◽  
Xavier Declèves ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Haematological Malignancy ◽  
External Validation ◽  
Predictive Performance ◽  
Paediatric Population ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
High Risk Population ◽  
Dosing Regimen

BackgroundChildren with haematological malignancy represent an identified subgroup of the paediatric population with specific pharmacokinetic parameters. In these patients, inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality, making optimization of the dosing regimen essential. As paediatric data are limited, our aim was to evaluate the population pharmacokinetics of teicoplanin in order to define the appropriate dosing regimen in this high-risk population.MethodsThe current dose of teicoplanin was evaluated in children with haematological malignancy. Population pharmacokinetics of teicoplanin was analysed using NONMEM software. The dosing regimen was optimised based on the final model.ResultsEighty-five children (age range: 0.5 to 16.9 years) were included. Therapeutic drug monitoring and opportunistic samples (n=143) were available for analysis. With the current recommended dose of 10 mg/kg/day, 41 children (48%) had sub-therapeutic steady-state trough concentrations (Css,min<10 mg/liter). A two-compartment pharmacokinetic model with first-order elimination was developed. Systematic covariate analysis identified that bodyweight (size) and creatinine clearance significantly influenced teicoplanin clearance. The model was validated internally. Its predictive performance was further confirmed in an external validation. In order to reach the target AUC of 750 mg·h/L, 18 mg/kg was required for infants, 14 mg/kg for children and 12 mg/kg for adolescents. A patient-tailored dose regimen was further developed and reduced variability in AUC and Css,min values compared to the mg/kg-basis dose, making the modelling approach an important tool for dosing individualization.ConclusionsThis first population pharmacokinetic study of teicoplanin in children with haematological malignancy provided evidence-based support to individualize teicoplanin therapy in this vulnerable population.

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