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 O13 Improved early vancomycin exposure in neonates using a population pharmacokinetic model-based vancomycin dosing regimen

2019 ◽  
Vol 104 (6) ◽  
pp. e6.1-e6
Author(s):  
A Smits ◽  
E De Saeger ◽  
A Vandendriessche ◽  
V Cossey ◽  
K Allegaert
Keyword(s):  
Clinical Characteristics ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Loading Dose ◽  
Dosing Regimen ◽  
Model Based ◽  
Postmenstrual Age ◽  
Dosing Regimens ◽  
Trough Levels

BackgroundWe previously documented that 2 published vancomycin dosing regimens resulted in subtherapeutic exposure in 66.3 and 76.2% of neonates.1 A new dosing regimen derived from a population pharmacokinetic (PK) analysis and using a loading dose, was implemented in our unit.2 We aimed to investigate if the new regimen results in improved vancomycin exposure (target trough 10–15 mg/L).MethodsClinical data and early (24 h after start) vancomycin therapeutic drug monitoring (TDM) in neonates receiving vancomycin for medical reasons, were retrospectively collected and pooled with 2 historical cohorts [cohort 1 (2011, n=193 observations), dosing based on postmenstrual age (PMA) and creatininemia and cohort 2 (2012, n=101 observations), dosing based on PMA and postnatal age (PNA)]. The new regimen [cohort 3 (2018, n=71 observations)] consists of a loading dose, followed by dosing based on birthweight, PNA and ibuprofen co-treatment [2]. Clinical characteristics and early TDM were compared across the cohorts using the Kruskal-Wallis Test. Results were significant if p< 0.05.ResultsClinical characteristics (cohort 1, 2 and 3 respectively) did not differ significantly across the cohorts. Median (IQ range) GA was 32.8 (28.4–37.6), 32.1 (28.5–37.5), 28 (26–38) weeks with p=0.097; PNA 13 (6–26), 12 (7–23), 14 (10–25) days with p=0.15 and creatininemia 0.43 (0.33–0.55), 0.49 (0.33–0.65), 0.45 (0.32–0.57) mg/dL with p=0.15. Median vancomycin trough level was 7.8 (5.1–11.3), 5.8 (4.1–8.7), 13.3 (9.9–17.3) mg/L with p< 0.0001. With the new regimen, 25.4% of trough levels was < 10 mg/L, 40.8% >15 mg/L, and 33.8% was on target, versus 23.3 and 19.8% on target in cohort 1 and 2 respectively.ConclusionA population PK model-based vancomycin dosing regimen using a loading dose, resulted in improved neonatal vancomycin exposure. Although only 25% of trough levels was subtherapeutic, dosing optimalisation for cases with supratherapeutic exposure is also needed, as well as further prospective validation.ReferencesVandendriessche, et al. Curr Ther Res Clin Exp 2014.Janssen, et al. AAC 2015.Disclosure(s)Nothing to disclose

scholarly journals Using Population Pharmacokinetics To Determine Gentamicin Dosing during Extended Daily Diafiltration in Critically Ill Patients with Acute Kidney Injury

2010 ◽  
Vol 54 (9) ◽  
pp. 3635-3640 ◽  
Author(s):  
Jason A. Roberts ◽  
Jonathan Field ◽  
Adam Visser ◽  
Rosemary Whitbread ◽  
Mandy Tallot ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Kidney Injury ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic

ABSTRACT The objective of the present prospective pharmacokinetic study was to describe the variability of plasma gentamicin concentrations in critically ill patients with acute kidney injury (AKI) necessitating extended daily diafiltration (EDD-f) using a population pharmacokinetic model and to subsequently perform Monte Carlo dosing simulations to determine which dose regimen achieves the pharmacodynamic targets the most consistently. We collected data from 28 gentamicin doses in 14 critically ill adult patients with AKI requiring EDD-f and therapeutic gentamicin. Serial plasma samples were collected. A population pharmacokinetic model was used to describe the pharmacokinetics of gentamicin and perform Monte Carlo simulations with doses of between 3 mg/kg of body weight and 7 mg/kg and at various time points before commencement of EDD-f to evaluate the optimal dosing regimen for achieving pharmacodynamic targets. A two-compartment pharmacokinetic model adequately described the gentamicin clearance while patients were on and off EDD-f. The plasma half-life of gentamicin during EDD-f was 13.8 h, whereas it was 153.4 h without EDD-f. Monte Carlo simulations suggest that dosing with 6 mg/kg every 48 h either 30 min or 1 h before the commencement of EDD-f results in 100% attainment of the target maximum concentration drug in plasma (<10 mg/liter) and sufficient attainment of the target area under the concentration-time curve from 0 to 24 h (AUC0-24; 70 to 120 mg·h/liter). None of the simulated dosing regimens satisfactorily achieved the targets of the minimum concentrations of drug in plasma (<1.0 mg/liter) at 24 h. In conclusion, dosing of gentamicin 30 min to 1 h before the commencement of an EDD-f treatment enables attainment of target peak concentrations for maximal therapeutic effect while enhancing drug clearance to minimize toxicity. Redosing in many patients should occur after 48 h, and we recommend the use of therapeutic drug monitoring to guide dosing to optimize achievement of the AUC0-24 targets.

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.

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.

A numerical study of the sedimentation of fibre suspensions

1998 ◽  
Vol 376 ◽  
pp. 149-182 ◽  
Author(s):  
MICHAEL B. MACKAPLOW ◽  
ERIC S. G. SHAQFEH
Keyword(s):  
Monte Carlo ◽  
Steady State ◽  
Monte Carlo Simulations ◽  
Numerical Study ◽  
Point Particle ◽  
Hydrodynamic Interactions ◽  
Dynamic Simulations ◽  
Slender Body Theory ◽  
Fibre Suspensions ◽  
The Mean

The sedimentation of fibre suspensions at low Reynolds number is studied using two different, but complementary, numerical simulation methods: (1) Monte Carlo simulations, which consider interparticle hydrodynamic interactions at all orders within the slender-body theory approximation (Mackaplow & Shaqfeh 1996), and (ii) dynamic simulations, which consider point–particle interactions and are accurate for suspension concentrations of nl3=1, where n and l are the number density and characteristic half-length of the fibres, respectively. For homogeneous, isotropic suspensions, the Monte Carlo simulations show that the hindrance of the mean sedimentation speed is linear in particle concentration up to at least nl3=7. The speed is well predicted by a new dilute theory that includes the effect of two-body interactions. Our dynamic simulations of dilute suspensions, however, show that interfibre hydrodynamic interactions cause the spatial and orientational distributions to become inhomogeneous and anisotropic. Most of the fibres migrate into narrow streamers aligned in the direction of gravity. This drives a downward convective flow within the streamers which serves to increase the mean fibre sedimentation speed. A steady-state orientation distribution develops which strongly favours fibre alignment with gravity. Although the distribution reaches a steady state, individual fibres continue to rotate in a manner that can be qualitatively described as a flipping between the two orientations aligned with gravity. The simulation results are in good agreement with published experimental data.

scholarly journals Population Pharmacokinetics of Continuous-Infusion Meropenem in Febrile Neutropenic Patients with Hematologic Malignancies: Dosing Strategies for Optimizing Empirical Treatment against Enterobacterales and P. aeruginosa

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 785
Author(s):  
Pier Giorgio Cojutti ◽  
Anna Candoni ◽  
Davide Lazzarotto ◽  
Carla Filì ◽  
Maria Zannier ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Continuous Infusion ◽  
Hematologic Malignancies ◽  
Population Pharmacokinetic Analysis ◽  
Empirical Treatment ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Dosing Strategies ◽  
Neutropenic Patients

A population pharmacokinetic analysis of continuous infusion (CI) meropenem was conducted in a prospective cohort of febrile neutropenic (FN) patients with hematologic malignancies. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed for identifying the most appropriate dosages for empirical treatment against common Enterobacterales and P. aeruginosa. The probability of target attainment (PTA) of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) ratio (Css/MIC) ≥1 and ≥4 at the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint of 2 mg/L were calculated. Cumulative fraction of response (CFR) against Enterobacterales and P. aeruginosa were assessed as well. PTAs and CFRs ≥ 90% were considered optimal. A total of 61 patients with 178 meropenem Css were included. Creatinine clearance (CLCR) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may grant optimal PTAs of Css/MIC ≥4 at the EUCAST clinical breakpoint. Optimal CFRs may be granted with these dosages against the Enterobacterales at Css/MIC ≥ 4 and against P. aeruginosa at Css/MIC ≥ 1. When dealing against P. aeruginosa at Css/MIC ≥ 4, only a dosage of 1.5 g q6h by CI may grant quasi-optimal CFR (around 80–87%). In conclusion, our findings suggest that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may maximize empirical treatment against Enterobacterales and P. aeruginosa among FN patients with hematologic malignancies having different degree of renal function.

scholarly journals Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates

2018 ◽  
Vol 62 (4) ◽  
pp. e01647-17 ◽  
Author(s):  
Sheng-Hsuan Tseng ◽  
Chuan Poh Lim ◽  
Qi Chen ◽  
Cheng Cai Tang ◽  
Sing Teang Kong ◽  
...  
Keyword(s):  
Steady State ◽  
Trough Concentration ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Vancomycin Trough ◽  
Trough Concentrations ◽  
The Relationship

ABSTRACT Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC24/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC24. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC24/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC24/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.

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.

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