scholarly journals Dosing regimen of meropenem for adults with severe burns: a population pharmacokinetic study with Monte Carlo simulations

2014 ◽  
Vol 70 (3) ◽  
pp. 882-890 ◽  
Author(s):  
A. Ramon-Lopez ◽  
J. M. Allen ◽  
A. H. Thomson ◽  
B. S. Dheansa ◽  
S. E. James ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Pharmacokinetic Study ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Population Pharmacokinetic Study ◽  
Severe Burns

scholarly journals Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice

2015 ◽  
Vol 59 (10) ◽  
pp. 6344-6351 ◽  
Author(s):  
A. Smits ◽  
R. F. W. De Cock ◽  
K. Allegaert ◽  
S. Vanhaesebrouck ◽  
M. Danhof ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Steady State ◽  
Monte Carlo Simulations ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Prospective Evaluation ◽  
Dosing Regimen ◽  
Model Based ◽  
Almost All ◽  
Trough Levels

ABSTRACTBased on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% ≤5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization.

PROSPECTIVE VALIDATION OF A MODEL-BASED DOSING REGIMEN FOR AMIKACIN IN NEONATES: FEASIBLE AND RELEVANT

2015 ◽  
Vol 101 (1) ◽  
pp. e1.40-e1
Author(s):  
Anne Smits ◽  
Roosmarijn De Cock ◽  
Karel Allegaert ◽  
Sophie Vanhaesebrouck ◽  
Meindert Danhof ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Model Based ◽  
Prediction Distribution ◽  
Before And After ◽  
Almost All ◽  
Trough Levels

IntroductionA neonatal amikacin dosing regimen was previously developed based on a population pharmacokinetic model. The aim of the current study was to prospectively validate this model-derived dosing regimen.MethodsFirst, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/L) and peak (>24 mg/L) levels. Secondly, observed concentrations were compared with model-predicted concentrations, whereby the results of an NPDE (normalized prediction distribution error) were considered as well. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (prescription errors and disease characteristics of outliers) were explored.ResultsIn 579 neonates [median (range) birth bodyweight 2285 (420–4850) g, postnatal age 2 (1–30) days, gestational age 34 (24–41) weeks], 90.5% of early peak levels reached 24 mg/L and 60.2% of trough levels was <3 mg/L (93.4% ≤5 mg/L). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations >24 mg/L were reached in almost all patients. Trough values <3 mg/L were documented in 78–100% and 45–96% of simulated cases, respectively, when ibuprofen was co-administered or not. Suboptimal trough levels were found in patient subgroups with postnatal age <14 days and current weight >2000g.ConclusionsProspective validation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Adapted dosing for patients with suboptimal trough levels was proposed. Besides improving dosing individualization, feasibility and relevance of neonatal prospective validation studies was demonstrated.

scholarly journals Pharmacokinetic Modeling of Voriconazole To Develop an Alternative Dosing Regimen in Children

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Silke Gastine ◽  
Thomas Lehrnbecher ◽  
Carsten Müller ◽  
Fedja Farowski ◽  
Peter Bader ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Modeling ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Concentration Data ◽  
Days Of Therapy ◽  
Dosing Regimens

ABSTRACT The pharmacokinetic variability of voriconazole (VCZ) in immunocompromised children is high, and adequate exposure, particularly in the first days of therapy, is uncertain. A population pharmacokinetic model was developed to explore VCZ exposure in plasma after alternative dosing regimens. Concentration data were obtained from a pediatric phase II study. Nonlinear mixed effects modeling was used to develop the model. Monte Carlo simulations were performed to test an array of three-times-daily (TID) intravenous dosing regimens in children 2 to 12 years of age. A two-compartment model with first-order absorption, nonlinear Michaelis-Menten elimination, and allometric scaling best described the data (maximal kinetic velocity for nonlinear Michaelis-Menten clearance [V max] = 51.5 mg/h/70 kg, central volume of distribution [V 1] = 228 liters/70 kg, intercompartmental clearance [Q] = 21.9 liters/h/70 kg, peripheral volume of distribution [V 2] = 1,430 liters/70 kg, bioavailability [F] = 59.4%, Km = fixed value of 1.15 mg/liter, absorption rate constant = fixed value of 1.19 h−1). Interindividual variabilities for V max, V 1, Q, and F were 63.6%, 45.4%, 67%, and 1.34% on a logit scale, respectively, and residual variability was 37.8% (proportional error) and 0.0049 mg/liter (additive error). Monte Carlo simulations of a regimen of 9 mg/kg of body weight TID simulated for 24, 48, and 72 h followed by 8 mg/kg two times daily (BID) resulted in improved early target attainment relative to that with the currently recommended BID dosing regimen but no increased rate of accumulation thereafter. Pharmacokinetic modeling suggests that intravenous TID dosing at 9 mg/kg per dose for up to 3 days may result in a substantially higher percentage of children 2 to 12 years of age with adequate exposure to VCZ early during treatment. Before implementation of this regimen in patients, however, validation of exposure, safety, and tolerability in a carefully designed clinical trial would be needed.

scholarly journals Pharmacokinetics of meropenem in septic patients on sustained low-efficiency dialysis: a population pharmacokinetic study

Critical Care ◽  
2018 ◽  
Vol 22 (1) ◽  
Author(s):  
Stephan Braune ◽  
Christina König ◽  
Jason A. Roberts ◽  
Axel Nierhaus ◽  
Oliver Steinmetz ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
Population Pharmacokinetic ◽  
Population Pharmacokinetic Study ◽  
Low Efficiency
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