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 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

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.

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 &gt;16 mg/L, cefoperazone is not a preferred choice.

scholarly journals A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants

2016 ◽  
Vol 60 (11) ◽  
pp. 6626-6634 ◽  
Author(s):  
Stéphanie Leroux ◽  
Jean-Michel Roué ◽  
Jean-Bernard Gouyon ◽  
Valérie Biran ◽  
Hao Zheng ◽  
...  
Keyword(s):  
High Performance ◽  
Sampling Strategy ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Dosing Regimen ◽  
Model Based ◽  
Young Infants

ABSTRACTCefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates (gestational age [GA] range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants.

scholarly journals Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

2014 ◽  
Vol 58 (8) ◽  
pp. 4718-4726 ◽  
Author(s):  
Ping Liu ◽  
Diane R. Mould
Keyword(s):  
Invasive Aspergillosis ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Institutional Review Boards ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
First Order ◽  
Two Compartment Model

ABSTRACTTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).

Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis

2021 ◽  
Author(s):  
Antonin Praet ◽  
Laurent Bourguignon ◽  
Florence Vetele ◽  
Valentine Breant ◽  
Charlotte Genestet ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dose Adjustment ◽  
Total Body Weight ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Two Compartment Model ◽  
Total Body

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC 24 /MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC 24 /MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

scholarly journals 1573. Population Pharmacokinetic Analyses for Cefepime in Adult and Pediatric Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S574-S575
Author(s):  
Jiajun Liu ◽  
Michael Neely ◽  
Jeffrey Lipman ◽  
Fekade B Sime ◽  
Jason Roberts ◽  
...  
Keyword(s):  
Rate Constant ◽  
Pediatric Patients ◽  
Validation Cohort ◽  
External Validation ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Information Criteria ◽  
Population Pharmacokinetic ◽  
Final Model ◽  
Two Compartment Model

Abstract Background Cefepime (CEF) is commonly used for adult and pediatric infections. Several studies have examined CEF’s pharmacokinetics (PK) in various populations; however, a unifying PK model for adult and pediatric subjects does not yet exist. We developed a combined population model for adult and pediatric patients and validated the model. Methods The initial model includes adult and pediatric patients with a rich cefepime sampling design. All adults received 2 g CEF while pediatric subjects received a mean of 49 (SD 5) mg/kg. One- and two-compartment models were considered as base models and were fit using a non-parametric adaptive grid algorithm within the Pmetrics package 1.5.2 (Los Angeles, CA) for R 3.5.1. Compartmental model selection was based on Akaike information criteria (AIC). Covariate relationships with PK parameters were visually inspected and mathematically assessed. Predictive performance was evaluated using bias and imprecision of the population and individual prediction models. External validation was conducted using a separate adult cohort. Results A total of 45 subjects (n = 9 adults; n = 36 pediatrics) were included in the initial PK model build and 12 subjects in the external validation cohort. Overall, the data were best described using a two-compartment model with volume of distribution (V) normalized to total body weight (TBW/70 kg) and an allometric scaled elimination rate constant (Ke) for pediatric subjects (AIC = 4,138.36). Final model observed vs. predicted plots demonstrated good fit (population R2 = 0.87, individual R2 = 0.97, Figure 1a and b). For the final model, the population median parameter values (95% credibility interval) were V0 (total volume of distribution), 11.7 L (10.2–14.6); Ke for adult, 0.66 hour−1 (0.38–0.78), Ke for pediatrics, 0.82 hour−1 (0.64–0.85), KCP (rate constant from central to peripheral compartment), 1.4 hour−1 (1.3–1.8), KPC (rate constant from peripheral to central compartment), 1.6 hour−1 (1.2–1.8). The validation cohort has 12 subjects, and the final model fit the data well (individual R2 = 0.75). Conclusion In this diverse group of adult and pediatrics, a two-compartment model described CEF PK well and was externally validated with a unique cohort. This model can serve as a population prior for real-time PK software algorithms. Disclosures All authors: No reported disclosures.

scholarly journals Population Pharmacokinetics and Dosing Simulation of Vancomycin Administered by Continuous Injection in Critically Ill Patient

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1228
Author(s):  
Romain Garreau ◽  
Benoît Falquet ◽  
Lisa Mioux ◽  
Laurent Bourguignon ◽  
Tristan Ferry ◽  
...  
Keyword(s):  
Critically Ill ◽  
External Validation ◽  
Ideal Body Weight ◽  
Intermittent Infusion ◽  
Compartment Model ◽  
Critically Ill Patient ◽  
Population Pharmacokinetic ◽  
Measured Concentration ◽  
Icu Patients ◽  
Final Model

Background: Vancomycin is widely used for empirical antimicrobial therapy in critically ill patients with sepsis. Continuous infusion (CI) may provide more stable exposure than intermittent infusion, but optimal dosing remains challenging. The aims of this study were to perform population pharmacokinetic (PK) analysis of vancomycin administered by CI in intensive care unit (ICU) patients to identify optimal dosages. Methods: Patients who received vancomycin by CI with at least one measured concentration in our center over 16 months were included, including those under continuous renal replacement therapy (CRRT). Population PK was conducted and external validation of the final model was performed in a dataset from another center. Simulations were conducted with the final model to identify the optimal loading and maintenance doses for various stages of estimated creatinine clearance (CRCL) and in patients on CRRT. Target exposure was defined as daily AUC of 400–600 mg·h/L on the second day of therapy (AUC24–48 h). Results: A two-compartment model best described the data. Central volume of distribution was allometrically scaled to ideal body weight (IBW), whereas vancomycin clearance was influenced by CRRT and CRCL. Simulations performed with the final model suggested a loading dose of 27.5 mg/kg of IBW. The maintenance dose ranged from 17.5 to 30 mg/kg of IBW, depending on renal function. Overall, simulation showed that 55.8% (95% CI; 47–64%) of patients would achieve the target AUC with suggested dosages. Discussion: A PK model has been validated for vancomycin administered by CI in ICU patients, including patients under CRRT. Our model-informed precision dosing approach may help for early optimization of vancomycin exposure in such patients.

scholarly journals Aminoglycosides in the Intensive Care Unit: What's New in Population PK Modeling?

2021 ◽  
Author(s):  
Alexandre Duong ◽  
Chantale Simard ◽  
Yi Le Wang ◽  
David R. Williamson ◽  
Amélie Marsot
Keyword(s):  
Intensive Care ◽  
External Validation ◽  
Compartment Model ◽  
Dosing Regimen ◽  
Mixed Effect ◽  
Icu Patients ◽  
Optimal Dosing ◽  
Pubmed Database ◽  
Dosing Regimens ◽  
Significant Covariates

Background Although aminoglycosides are often used as treatment for Gram-Negative infections, optimal dosing regimens remains unclear, especially in ICU patients. This is due to a large between- and within-subject variability in the aminoglycosides&rsquo; pharmacokinetics in this population. Objective The review provides comprehensive data on the pharmacokinetics of aminoglycosides in patients hospitalized in ICU by summarizing all published PopPK models in ICU patients for amikacin, gentamicin, and tobramycin. The objective was to determine the presence of a consensus on the structural model used, significant covariates included, and therapeutic targets considered during dosing regimen simulations. Methods A literature search was conducted from the Medline/PubMed database, using the terms: &lsquo;amikacin&rsquo;, &rsquo;gentamicin&rsquo;, &rsquo;tobramycin&rsquo;, &lsquo;pharmacokinetic(s)&rsquo;, nonlinear mixed effect&rsquo;, population&rsquo;, &lsquo;intensive care&rsquo; and &lsquo;critically ill&rsquo;. Results Nineteen articles were retained where amikacin, gentamicin and tobramycin pharmacokinetics were described in six, eleven and five models, respectively. Two-compartment model best described amikacin and tobramycin pharmacokinetics, whereas one-compartment model majorly described gentamicin pharmacokinetics. The most recurrent significant covariates were renal clearance and bodyweight. Across all aminoglycosides, mean interindividual variability in clearance and volume of distribution were 41.6% and 22.0%, respectively. A common consensus for an optimal dosing regimen for each aminoglycoside was not reached. Conclusion This review showed models developed for amikacin, from 2015 until now and for gentamicin and tobramycin from the past decades. Despite growing challenges of external evaluation, the latter should be more considered during model development. Further research including new covariates, additional simulated dosing regimens and external validation should be considered to better understand aminoglycosides pharmacokinetics in ICU patients.

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