scholarly journals Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2170
Author(s):  
Femke de Velde ◽  
Brenda C. M. de Winter ◽  
Michael N. Neely ◽  
Jan Strojil ◽  
Walter M. Yamada ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
External Validation ◽  
Predictive Performance ◽  
Nonparametric Model ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Population Pharmacokinetic Modeling ◽  
Nonparametric Models ◽  
Dosing Regimens

Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients and (2) the probability of target attainment (PTA) calculations using simulations of both models. The M&S software used was NONMEM 7.2 (parametric) and Pmetrics 1.5.2 (nonparametric). The external predictive performance of both models was adequate for eGFRs ≥ 78 mL/min but insufficient for lower eGFRs, indicating that the models (developed using a population with eGFR ≥ 60 mL/min) could not be extrapolated to lower eGFRs. Simulations were performed for three dosing regimens and three eGFRs (90, 120, 150 mL/min). Fifty percent of the PTA results were similar for both models, while for the other 50% the nonparametric model resulted in lower MICs. This was explained by a higher estimated between-subject variability of the nonparametric model. Simulations indicated that 1000 mg q6h is suitable to reach MICs of 2 mg/L for eGFRs of 90–120 mL/min. For MICs of 4 mg/L and for higher eGFRs, dosing recommendations are missing due to largely different PTA values per model. The consequences of the different modeling approaches in clinical practice should be further investigated.

scholarly journals Population Pharmacokinetics of Piperacillin following Continuous Infusion in Critically Ill Patients and Impact of Renal Function on Target Attainment

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Vibeke Klastrup ◽  
Anders Thorsted ◽  
Merete Storgaard ◽  
Steffen Christensen ◽  
Lena E. Friberg ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Bacterial Infections ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Content Type ◽  
Daily Dose ◽  
Linear Elimination ◽  
Severe Infections

ABSTRACT Pharmacokinetic changes are often seen in patients with severe infections. Administration by continuous infusion has been suggested to optimize antibiotic exposure and pharmacokinetic/pharmacodynamic (PK/PD) target attainment for β-lactams. In an observational study, unbound piperacillin concentrations (n = 196) were assessed in 78 critically ill patients following continuous infusion of piperacillin-tazobactam (ratio 8:1). The initial dose of 8, 12, or 16 g (piperacillin component) was determined by individual creatinine clearance (CRCL). Piperacillin concentrations were compared to the EUCAST clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/PD targets were evaluated: 100% free time (fT) > 1× MIC and 100% fT > 4× MIC. A population pharmacokinetic model was developed using NONMEM 7.4.3 consisting of a one-compartment disposition model with linear elimination separated into nonrenal and renal (linearly increasing with patient CRCL) clearances. Target attainment was predicted and visualized for all individuals based on the utilized CRCL dosing algorithm. The target of 100% fT > 1× MIC was achieved for all patients based on the administered dose, but few patients achieved the target of 100% fT > 4× MIC. Probability of target attainment for a simulated cohort of patients showed that increasing the daily dose by 4-g increments (piperacillin component) did not result in substantially improved target attainment for the 100% fT > 4× MIC target. To conclude, in patients with high CRCL combined with high-MIC bacterial infections, even a continuous infusion (CI) regimen with a daily dose of 24 g may be insufficient to achieve therapeutic concentrations.

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.

scholarly journals Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling

2015 ◽  
Vol 60 (2) ◽  
pp. 1013-1021 ◽  
Author(s):  
Esther J. H. Janssen ◽  
Pyry A. J. Välitalo ◽  
Karel Allegaert ◽  
Roosmarijn F. W. de Cock ◽  
Sinno H. P. Simons ◽  
...  
Keyword(s):  
Pediatric Population ◽  
External Validation ◽  
Population Pharmacokinetic ◽  
Target Area ◽  
Pharmacokinetic Models ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Model Based ◽  
Dosing Algorithm ◽  
Dosing Regimens

ABSTRACTBecause of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC24/MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged <1 year, doses between 32 and 60 mg/kg/day over four doses are proposed, while above 1 year of age, 60 mg/kg/day seems appropriate. As the time to reach steady-state concentrations varies from 155 h in preterm infants to 36 h in children aged >1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged <1 year. For children aged 1 year and older, the currently advised maintenance dose of 60 mg/kg/day seems appropriate.

scholarly journals Population Pharmacokinetics and Pharmacodynamics of Continuous versus Short-Term Infusion of Imipenem-Cilastatin in Critically Ill Patients in a Randomized, Controlled Trial

2007 ◽  
Vol 51 (9) ◽  
pp. 3304-3310 ◽  
Author(s):  
Samir G. Sakka ◽  
Anna K. Glauner ◽  
Jürgen B. Bulitta ◽  
Martina Kinzig-Schippers ◽  
Wolfgang Pfister ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Population Pharmacokinetic ◽  
Beta Lactams ◽  
Target Attainment ◽  
Short Term ◽  
Randomized Controlled ◽  
Drug Concentrations

ABSTRACT Beta-lactams are regularly administered in intermittent short-term infusions. The percentage of the dosing interval during which free drug concentrations exceed the MIC (fT >MIC) is the measure of drug exposure that best correlates with clinical outcome for beta-lactams. Therefore, administration by continuous infusion has gained increasing interest recently. We studied 20 critically ill patients with nosocomial pneumonia and investigated whether continuous infusion with a reduced total dose, compared to the standard regimen of intermittent short-term infusion, results in a superior probability of target attainment as assessed by the fT >MIC value of imipenem. In this prospective, randomized, controlled clinical study, patients received either a loading dose of 1 g/1 g imipenem and cilastatin (as a short-term infusion) at time zero, followed by 2 g/2 g imipenem-cilastatin per 24 h as a continuous infusion for 3 days (n = 10), or 1 g/1 g imipenem-cilastatin three times per day as a short-term infusion for 3 days (total daily dose, 3 g/3 g; n = 10). Imipenem concentrations in plasma were determined by using a validated liquid chromatography-tandem mass spectrometry assay. A two-compartment open model was employed for population pharmacokinetic modeling. We simulated 10,000 intensive-care-unit patients via Monte Carlo simulations for pharmacodynamic evaluation using the target 40% fT >MIC. The probability of target attainment by MIC for intermittent infusion was robust (>90%) up to MICs of 1 to 2 mg/liter. The corresponding value for continuous infusion was 2 to 4 mg/liter. Although all 20 patients had an fT >MIC of 100%, 3 patients died. Patient survival was best described by employing a sepsis-related organ failure assessment score as a covariate in a logistic regression analysis. Larger clinical trials are warranted for evaluation of continuous infusions at a reduced dose of imipenem for critically ill patients.

scholarly journals Amikacin Initial Dose in Critically Ill Patients: a Nonparametric Approach To Optimize A Priori Pharmacokinetic/Pharmacodynamic Target Attainments in Individual Patients

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Clément Boidin ◽  
Laurent Bourguignon ◽  
Sabine Cohen ◽  
Claire Roger ◽  
Jean-Yves Lefrant ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
A Priori ◽  
Predictive Performance ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Data Set ◽  
Nonparametric Approach ◽  
The Right

ABSTRACT Amikacin is commonly used for probabilistic antimicrobial therapy in critically ill patients with sepsis. Its narrow therapeutic margin makes it challenging to determine the right individual dose that ensures the highest efficacy target attainment rate (TAR) in this setting. This study aims to develop a new initial dosing approach for amikacin by optimizing the a priori TAR in this population. A population pharmacokinetic model was built with a learning data set from critically ill patients who received amikacin. It was then used to design an initial dosing approach maximizing a priori TAR for a target ratio of ≥8 for the peak concentration to the MIC (Cmax/MIC) or of ≥75 for the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC0–24/MIC). In the 166 patients included, 53% had amikacin Cmax of ≥64 mg/liter with a median dose of 23.4 mg/kg. A two-compartment model with creatinine clearance and body surface area as covariates best described the data and showed good predictive performance. Our dosing approach was successful in optimizing TAR for Cmax/MIC, with a rate of 92.9% versus 67.9% using a 30-mg/kg regimen, based on an external subset of data and assuming a MIC of 8 mg/liter. Mean optimal doses were higher (3.5 ± 0.5 g) than with the 30-mg/kg regimen (2.1 ± 0.3 g). Suggested doses varied with the MIC, the target index, and desired TAR threshold. A dosing algorithm based on the method is proposed for a large range of patient covariates. Clinical studies are necessary to confirm efficacy and safety of this optimized dosing approach.

scholarly journals Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients

2016 ◽  
Vol 60 (9) ◽  
pp. 5254-5261 ◽  
Author(s):  
Max Taubert ◽  
Michael Zoller ◽  
Barbara Maier ◽  
Sebastian Frechen ◽  
Christina Scharf ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Strong Predictor ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Serum Samples ◽  
Time Curve ◽  
Blood Concentrations ◽  
Registration Number

ABSTRACTAdequate linezolid blood concentrations have been shown to be associated with an improved clinical outcome. Our goal was to assess new predictors of inadequate linezolid concentrations often observed in critically ill patients. Fifty-two critically ill patients with severe infections receiving standard dosing of linezolid participated in this prospective observational study. Serum samples (median, 32 per patient) were taken on four consecutive days, and total linezolid concentrations were quantified. Covariates influencing linezolid pharmacokinetics were identified by multivariate analysis and a population pharmacokinetic model. Target attainment (area under the concentration-time curve over 12 h [AUC12]/MIC ratio of >50; MIC = 2 mg/liter) was calculated for both the study patients and a simulated independent patient group (n= 67,000). Target attainment was observed for only 36% of the population on both days 1 and 4. Independent covariates related to significant decreases of linezolid concentrations included higher weight, creatinine clearance rates, and fibrinogen and antithrombin concentrations, lower concentrations of lactate, and the presence of acute respiratory distress syndrome (ARDS). Linezolid clearance was increased in ARDS patients (by 82%) and in patients with elevated fibrinogen or decreased lactate concentrations. In simulated patients, most covariates, including fibrinogen and lactate concentrations and weight, showed quantitatively minor effects on target attainment (difference of ≤9% between the first and fourth quartiles of the respective parameters). In contrast, the presence of ARDS had the strongest influence, with only ≤6% of simulated patients reaching this target. In conclusion, the presence of ARDS was identified as a new and strong predictor of insufficient linezolid concentrations, which might cause treatment failure. Insufficient concentrations might also be a major problem in patients with combined alterations of other covariate parameters. (This study has been registered at ClinicalTrials.gov under registration number NCT01793012.)

scholarly journals Are Standard Dosing Regimens of Ceftriaxone Adapted for Critically Ill Patients with Augmented Creatinine Clearance?

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Julien Ollivier ◽  
Cédric Carrié ◽  
Nicolas d’Houdain ◽  
Sarah Djabarouti ◽  
Laurent Petit ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Creatinine Clearance ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Free Fraction ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Target Attainment ◽  
Dosing Regimens

ABSTRACT The objective of the present study was to determine whether augmented renal clearance (ARC) impacts negatively on ceftriaxone pharmacokinetic (PK)/pharmacodynamic (PD) target attainment in critically ill patients. Over a 9-month period, all critically ill patients treated with ceftriaxone were eligible. During the first 3 days of antimicrobial therapy, every patient underwent 24-h creatinine clearance (CLCR) measurements and therapeutic drug monitoring of unbound ceftriaxone. ARC was defined by a CLCR of ≥150 ml/min. Empirical underdosing was defined by a trough unbound ceftriaxone concentration under 2 mg/liter (percentage of the time that the concentration of the free fraction of drug remained greater than the MIC [fT>MIC], 100%). Monte Carlo simulation (MCS) was performed to determine the probability of target attainment (PTA) of different dosing regimens for various MICs and three groups of CLCR (<150, 150 to 200, and >200 ml/min). Twenty-one patients were included. The rate of empirical ceftriaxone underdosing was 62% (39/63). A CLCR of ≥150 ml/min was associated with empirical target underdosing with an odds ratio (OR) of 8.8 (95% confidence interval [CI] = 2.5 to 30.7; P < 0.01). Ceftriaxone PK concentrations were best described by a two-compartment model. CLCR was associated with unbound ceftriaxone clearance (P = 0.02). In the MCS, the proportion of patients who would have failed to achieve a 100% fT>MIC was significantly higher in ARC patients for each dosage regimen (OR = 2.96; 95% CI = 2.74 to 3.19; P < 0.01). A dose of 2 g twice a day was best suited to achieve a 100% fT>MIC. When targeting a 100% fT>MIC for the less susceptible pathogens, patients with a CLCR of ≥150 ml/min remained at risk of empirical ceftriaxone underdosing. These data emphasize the need for therapeutic drug monitoring in ARC patients.

scholarly journals A Simulation Study Reveals Lack of Pharmacokinetic/Pharmacodynamic Target Attainment in De-escalated Antibiotic Therapy in Critically Ill Patients

2015 ◽  
Vol 59 (8) ◽  
pp. 4689-4694 ◽  
Author(s):  
Mieke Carlier ◽  
Jason A. Roberts ◽  
Veronique Stove ◽  
Alain G. Verstraete ◽  
Jeffrey Lipman ◽  
...  
Keyword(s):  
Antibiotic Therapy ◽  
Critically Ill ◽  
Simulation Study ◽  
Broad Spectrum ◽  
Critically Ill Patients ◽  
Primary Objective ◽  
Distribution Data ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Data Set

ABSTRACTDe-escalation of empirical antibiotic therapy is often included in antimicrobial stewardship programs in critically ill patients, but differences in target attainment when antibiotics are switched are rarely considered. The primary objective of this study was to compare the fractional target attainments of contemporary dosing of empirical broad-spectrum β-lactam antibiotics and narrower-spectrum antibiotics for a number pathogens for which de-escalation may be considered. The secondary objective was to determine whether alternative dosing strategies improve target attainment. We performed a simulation study using published population pharmacokinetic (PK) studies in critically ill patients for a number of broad-spectrum β-lactam antibiotics and narrower-spectrum antibiotics. Simulations were undertaken using a data set obtained from critically ill patients with sepsis without absolute renal failure (n= 49). The probability of target attainment of antibiotic therapy for different microorganisms for which de-escalation was applied was analyzed. EUCAST MIC distribution data were used to calculate fractional target attainment. The probability that therapeutic exposure will be achieved was lower for the narrower-spectrum antibiotics with conventional dosing than for the broad-spectrum alternatives and could drastically be improved with higher dosages and different modes of administrations. For a selection of microorganisms, the probability that therapeutic exposure will be achieved was overall lower for the narrower-spectrum antibiotics using conventional dosing than for the broad-spectrum antibiotics.

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