In this paper, kinetic modeling techniques for complex chemical processes are reviewed. After a brief historical overview of chemical kinetics, an overview is given of the theoretical background of ...kinetic modeling of elementary steps and of multistep reactions. Classic lumping techniques are introduced and analyzed. Two examples of lumped kinetic models (atmospheric gasoil hydrotreating and residue hydroprocessing) developed at IFP Energies nouvelles (IFPEN) are presented. The largest part of this review describes advanced kinetic modeling strategies, in which the molecular detail is retained, i.e. the reactions are represented between molecules or even subdivided into elementary steps. To be able to retain this molecular level throughout the kinetic model and the reactor simulations, several hurdles have to be cleared first: (i) the feedstock needs to be described in terms of molecules, (ii) large reaction networks need to be automatically generated, and (iii) a large number of rate equations with their rate parameters need to be derived. For these three obstacles, molecular reconstruction techniques, deterministic or stochastic network generation programs, and single-event micro-kinetics and/or linear free energy relationships have been applied at IFPEN, as illustrated by several examples of kinetic models for industrial refining processes.
Dans cet article, les techniques de modélisation cinétique des processus chimiques complexes sont examinées. Après un bref aperçu historique de la cinétique chimique, un aperçu des bases théoriques de la modélisation cinétique d’étapes élémentaires et de réactions globales est présenté. Les techniques classiques de regroupement (lumping) sont ensuite présentées et analysées. Deux exemples de modèles cinétiques regroupés (pour l’hydrotraitement de gazole atmosphérique et pour l’hydrotraitement de résidus) développés à IFP Energies nouvelles (IFPEN) sont présentés. La plus grande partie de cette revue décrit des stratégies avancées de modélisation cinétique, dans lesquelles le détail moléculaire est retenu : les réactions entre les molécules sont représentées ou même subdivisées en étapes élémentaires. Pour être en mesure de conserver ce niveau moléculaire à la fois dans le modèle cinétique et dans les simulations de réacteurs, plusieurs obstacles doivent d’abord être éliminés : (i) la charge doit être décrite en termes de molécules, (ii) les grands réseaux réactionnels doivent être générés automatiquement et (iii) un grand nombre d’équations de vitesse avec leurs paramètres de vitesse doit être dérivé. Pour ces trois obstacles, des techniques de reconstruction moléculaire, des programmes de génération de réseaux déterministes ou stochastiques, et des modèles microcinétiques basés sur des événements constitutifs (single events) et/ou des relations linéaires d’énergie libre (Linear Free Energy Relationships) ont été utilisés à IFPEN, comme illustré par plusieurs exemples de modèles cinétiques pour des procédés de raffinage industriels.
•An ultrafast UPLC–MS/MS method was described to measure 5 β-lactam antibiotics.•Sample preparation consisted of protein denaturation and dilution of the supernatant.•Runtime was only 2.5min.•The ...method was fully validated.•A method comparison showed comparable results to our previous published assay.
There is an increasing interest in monitoring plasma concentrations of β-lactam antibiotics. The objective of this work was to develop and validate a fast ultra-performance liquid chromatographic method with tandem mass spectrometric detection (UPLC–MS/MS) for simultaneous quantification of amoxicillin, cefuroxime, ceftazidime, meropenem and piperacillin with minimal turn around time. Sample clean-up included protein precipitation with acetonitrile containing 5 deuterated internal standards, and subsequent dilution of the supernatant with water after centrifugation. Runtime was only 2.5min. Chromatographic separation was performed on a Waters Acquity UPLC system using a BEH C18 column (1.7μm, 100mm×2.1mm) applying a binary gradient elution of water and methanol both containing 0.1% formic acid and 2mmol/L ammonium acetate on a Water TQD instrument in MRM mode. All compounds were detected in electrospray positive ion mode and could be quantified between 1 and 100mg/L for amoxicillin and cefuroxime, between 0.5 and 80mg/L for meropenem and ceftazidime, and between 1 and 150mg/L for piperacillin. The method was validated in terms of precision, accuracy, linearity, matrix effect and recovery and has been compared to a previously published UPLC–MS/MS method.
A Monte Carlo approach is used to generate 2D and 3D networks of randomly connected cylindrical pores with a variety of configurations. These networks are created to represent the gamma‐alumina ...supports of hydrotreating catalysts. Textural properties from generated pore networks are compared with experimental values of porosity, specific surface area, and specific pore volume. The experimental properties were estimated using a helium pycnometer and nitrogen sorption isotherms for five gamma‐alumina samples. Simulated and experimental textural properties concur. Internal diffusion is simulated by 1D Fick diffusion within each pore of the network. A macroscopic diffusion parameter for vacuum distillate type molecules, previously obtained by inverse liquid chromatography and by pulsed‐field gradient nuclear magnetic resonance experiments on alumina samples, is predicted and confronted with experimental values. Diffusional properties are in good agreement when considering two hierarchically organized porous domains.
Hierarchical pore networks are able to correctly represent the tortuosity of gamma‐aluminas, while random pore networks with appropriate textural properties cannot.
Correct antibiotic dosing remains a challenge for the clinician. The aim of this study was to assess the influence of augmented renal clearance on pharmacokinetic/pharmacodynamic target attainment in ...critically ill patients receiving meropenem or piperacillin/tazobactam, administered as an extended infusion.
This was a prospective, observational, pharmacokinetic study executed at the medical and surgical intensive care unit at a large academic medical center. Elegible patients were adult patients without renal dysfunction receiving meropenem or piperacillin/tazobactam as an extended infusion. Serial blood samples were collected to describe the antibiotic pharmacokinetics. Urine samples were taken from a 24-hour collection to measure creatinine clearance. Relevant data were drawn from the electronic patient file and the intensive care information system.
We obtained data from 61 patients and observed extensive pharmacokinetic variability. Forty-eight percent of the patients did not achieve the desired pharmacokinetic/pharmacodynamic target (100% fT>MIC), of which almost 80% had a measured creatinine clearance>130 mL/min. Multivariate logistic regression demonstrated that high creatinine clearance was an independent predictor of not achieving the pharmacokinetic/pharmacodynamic target. Seven out of nineteen patients (37%) displaying a creatinine clearance>130 mL/min did not achieve the minimum pharmacokinetic/pharmacodynamic target of 50% fT>MIC.
In this large patient cohort, we observed significant variability in pharmacokinetic/pharmacodynamic target attainment in critically ill patients. A large proportion of the patients without renal dysfunction, most of whom displayed a creatinine clearance>130 mL/min, did not achieve the desired pharmacokinetic/pharmacodynamic target, even with the use of alternative administration methods. Consequently, these patients may be at risk for treatment failure without dose up-titration.
•Piperacillin population pharmacokinetic models mainly rely on intermittent infusion (II) data.•II PK models may underestimate piperacillin continuous infusion (CI) clearance.•High-dose (24 g/24 h) ...piperacillin CI may not always ensure adequate exposure.
Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when drug clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g. 16 g/24 h or more) are simulated. Therefore, the purpose of this study was to describe the population pharmacokinetics of piperacillin when infused continuously in critically ill patients. For this analysis, 270 plasma samples from 110 critically ill patients receiving piperacillin were available for population pharmacokinetic model building. A one-compartment model with linear clearance best described the concentration–time data. The mean ± standard deviation parameter estimates were 8.38 ± 9.91 L/h for drug clearance and 25.54 ± 3.65 L for volume of distribution. Creatinine clearance improved the model fit and was supported for inclusion as a covariate. In critically ill patients with renal clearance higher than 90 mL/min/1.73 m2, a high-dose continuous infusion of 24 g/24 h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT>4 x MIC) against susceptible Pseudomonas aerginosa isolates (MIC ≤16 mg/L). These findings suggest that merely increasing the dose of piperacillin, even with continuous infusion, may not always result in adequate piperacillin exposure. This should be confirmed by evaluating piperacillin target attainment rates in critically ill patients exhibiting high renal clearance.
Abstract
Background
Several population pharmacokinetic (PopPK) models for meropenem dosing in ICU patients are available. It is not known to what extent these models can predict meropenem ...concentrations in an independent validation dataset when meropenem is infused continuously.
Patients and methods
A PopPK model was developed with concentration–time data collected from routine care of 21 ICU patients (38 samples) receiving continuous infusion meropenem. The predictability of this model and seven other published PopPK models was studied using an independent dataset that consisted of 47 ICU patients (161 samples) receiving continuous infusion meropenem. A statistical comparison of imprecision (mean square prediction error) and bias (mean prediction error) was conducted.
Results
A one-compartment model with linear elimination and creatinine clearance as a covariate of clearance best described our data. The mean ± SD parameter estimate for CL was 9.89 ± 3.71 L/h. The estimated volume of distribution was 48.1 L. The different PopPK models showed a bias in predicting serum concentrations from the validation dataset that ranged from −8.76 to 7.06 mg/L. Imprecision ranged from 9.90 to 42.1 mg/L.
Conclusions
Published PopPK models for meropenem vary considerably in their predictive performance when validated in an external dataset of ICU patients receiving continuous infusion meropenem. It is necessary to validate PopPK models in a target population before implementing them in a therapeutic drug monitoring program aimed at optimizing meropenem dosing.
Purpose
There is variability in the pharmacokinetics (PK) of antibiotics (AB) in critically ill patients. Therapeutic drug monitoring (TDM) could overcome this variability and increase PK target ...attainment. The objective of this study was to analyse the effect of a dose-adaption strategy based on daily TDM on target attainment.
Methods
This was a prospective, partially blinded, and randomised controlled trial in patients with normal kidney function treated with meropenem (MEM) or piperacillin/tazobactam (PTZ). The intervention group underwent daily TDM, with dose adjustment when necessary. The predefined PK/pharmacodynamic (PK/PD) target was 100 %
f
T
>4MIC
percentage of time during a dosing interval that the free (
f
) drug concentration exceeded 4 times the MIC. The control group received conventional treatment. The primary endpoint was the proportion of patients that reached 100 %
f
T
>4MIC
and 100 %
f
T
>MIC
at 72 h.
Results
Forty-one patients (median age 56 years) were included in the study. Pneumonia was the primary infectious diagnosis. At baseline, 100 %
f
T
>4MIC
was achieved in 21 % of the PTZ patients and in none of the MEM patients; 100 %
f
T
>MIC
was achieved in 71 % of the PTZ patients and 46 % of the MEM patients. Of the patients in the intervention group, 76 % needed dose adaptation, and five required an additional increase. At 72 h, target attainment rates for 100 %
f
T
>4MIC
and 100 %
f
T
>MIC
were higher in the intervention group: 58 vs. 16 %,
p
= 0.007 and 95 vs. 68 %,
p
= 0.045, respectively.
Conclusions
Among critically ill patients with normal kidney function, a strategy of dose adaptation based on daily TDM led to an increase in PK/PD target attainment compared to conventional dosing.
•Piperacillin and meropenem concentrations are low but measurable in oral fluid of ICU patients.•Correlation was poor between oral fluid and both total and unbound plasma piperacillin ...concentrations.•Dispersion of antibiotic concentrations was greater in oral fluid than in blood.•Oral fluid from non-intubated ICU patients cannot be recommended for TDM.
Therapeutic drug monitoring (TDM) of β-lactam antibiotics may be used to optimize dosing for patients in the intensive care unit (ICU). A noninvasive matrix such as oral fluid may be interesting in selected patient groups. We compared the oral fluid concentrations of piperacillin and meropenem with the respective unbound and total concentrations in plasma. A secondary objective was to evaluate feasibility of the collection of oral fluid samples in this specific patient population.
The study included 20 non-intubated ICU patients, age 22 to 77 y, receiving piperacillin or meropenem via continuous intravenous infusion. The standard protocol consisted of collecting a paired plasma-oral fluid sample for 3 consecutive days. Oral fluid was obtained from the patients using a standardized procedure by spitting in a plastic container after 2 min of gathering oral fluid in the mouth.
Antibiotic concentrations of piperacillin and meropenem are measurable, albeit very low, in unstimulated oral fluid of ICU patients. For piperacillin, a poor correlation was found between oral fluid and both total and unbound plasma concentrations (Spearman’s correlation coefficients (Rs) 0.46 and 0.48 respectively). For meropenem this correlation was better (Rs for oral fluid versus total and unbound plasma meropenem concentration 0.92 and 0.93 respectively). Dispersion of antibiotic concentrations was greater in oral fluid than in blood. Collecting oral fluid samples was difficult in non-intubated ICU patients.
Oral fluid from non-intubated ICU patients, obtained through a standardized procedure, cannot be recommended as an alternative matrix for quantitative meropenem or piperacillin TDM.
Beta-lactam antibiotics are of vital importance for the treatment of infections in a broad range of patients. Although most systemically administered antibiotics will be excreted renally, a fraction ...will reach the gastro-intestinal tract, affecting the intestinal microbiome by eradicating a wide range of bacterial species while facilitating the growth of antimicrobial-resistant species. A better understanding of the kinetics of beta-lactam antibiotics in the gastro-intestinal tract is essential to study their role in the development of antibiotic resistance in bacteria and to help develop future therapies to prevent damage to, or restore, the intestinal microbiome.
Analysis of beta-lactam antibiotics in faeces is particularly challenging due to the heterogeneous nature of the matrix, rapid degradation of some beta-lactam antibiotics in faeces and very strong ion suppression when using mass spectrometry. Sample preparation was optimized using a sequential strategy of experimental designs. It resulted in lyophilization, a MOPS buffer system and the addition of the beta-lactamase inhibitor avibactam to minimize degradation of antibiotics allowing sensitive quantification. The developed liquid chromatography method with high-resolution mass spectrometric detection was successfully validated according to bioanalytical EMA guidelines and had a linear range of 1–200 μg g−1 lyophilized faeces for amoxicillin, piperacillin and meropenem; and 0.5–100 μg g−1 lyophilized faeces for tazobactam. Despite the highly complex and heterogeneous composition of faeces, the accuracy (0.1–15%) and precision (1.7–12.1%) were in line with those obtained for quantification methods of beta-lactam antibiotics in plasma, the golden standard matrix for therapeutic drug monitoring. The applicability of the method was illustrated by successful quantification of piperacillin and tazobactam in faeces from an intensive care unit patient receiving piperacillin/tazobactam in a continuous intravenous infusion. Both piperacillin and tazobactam were still present six days after discontinuation of the therapy.
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•Sensitive quantification of beta-lactam antibiotics in faeces.•Optimized sample preparation countering heterogeneous matrix and rapid degradation.•Applied to faecal samples from ICU patient receiving piperacillin/tazobactam.
Highlights • Pharmacokinetics may be severely altered in special patient populations. • Therapeutic drug monitoring might be useful to optimise dosing. • No commercial assays are currently available. ...• A systematic review was performed of all published methods.
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