Effect of Therapeutic Plasma Exchange on Itraconazole Pharmacokinetics: A Case Study.

ABSTRACT: The authors present the case of a 34-year-old male patient who underwent therapeutic plasma exchange (TPE) for amyopathic dermatomyositis. Immunosuppression resulted in Aspergillus lentulus pulmonary infection , requiring treatment with super bioavailable-itraconazole. Therapeutic itraconazole concentrations were attained after 2 weeks of treatment after dose adjustments. Interestingly, a substantial reduction in plasma itraconazole concentration was observed during TPE, which was attributed to an insufficient delay between the dosing of itraconazole and TPE initiation. Furthermore, there was an increase in plasma concentration post-TPE, which presumably reflects the redistribution of itraconazole from peripheral compartments back into plasma. This was confirmed by sampling of the TPE plasmapheresate, which revealed that changes in plasma concentration overestimated itraconazole clearance. These findings highlight that the pharmacokinetics of itraconazole are altered during TPE, which should be considered when timing drug administration and obtaining plasma concentrations.

Teaching a New Dog Old Tricks: Ultrafast Liquid Chromatography/Tandem-Mass Spectrometry Analysis of Nine ß-Lactam Antibiotics for Improved Therapeutic Drug Monitoring.

BACKGROUND: Therapeutic drug monitoring (TDM) of ß-lactam antibiotics provides critical knowledge in hospital intensive care unit environments to support dosing within the narrow window between therapeutic failure and toxicity. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the most suitable analytical technique for these drugs; however, clinicians, patients, and laboratories would benefit from shortening the timeframe between the collection of samples and reporting of results. METHODS: The authors developed a very rapid LC-MS/MS method for 9 ß-lactam antimicrobial drugs on a commercial core-shell reverse-phase LC column by exploiting the performance of such stationary phase materials at a high mobile-phase linear velocity and using a simple flow split to optimize ionization conditions in the mass spectrometer ion source. The method's performance was assessed using a currently validated routine LC-MS/MS assay performed on the same instrument. RESULTS: Routine ß-lactam assays were reduced from >6 minutes per sample to less than 2 minutes with improved chromatographic resolution, while still maintaining acceptable analytical performance (average correlation coefficient: 0.99670, interday imprecision: 2.0%-10.8%, and bias: -1.68%), hence generating results in agreement with an existing validated method for patient and quality assurance program samples. CONCLUSIONS: Time-critical results, such as those for ß-lactam antimicrobials, may be reported by the TDM laboratory several hours earlier than current methods allow, providing improved patient care and generating capacity on LC-MS/MS instruments for larger batch sizes and/or additional assays. The simple-to-implement technique demonstrated in this study may be applicable to other TDM assays or any LC-MS/MS method where faster turnaround times are desirable.

Optimal Practice for Vancomycin Therapeutic Drug Monitoring: Position Statement From the Anti-infectives Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

ABSTRACT: Individualization of vancomycin dosing based on therapeutic drug monitoring (TDM) data is known to improve patient outcomes compared with fixed or empirical dosing strategies. There is increasing evidence to support area-under-the-curve (AUC24)-guided TDM to inform vancomycin dosing decisions for patients receiving therapy for more than 48 hours. It is acknowledged that there may be institutional barriers to the implementation of AUC24-guided dosing, and additional effort is required to enable the transition from trough-based to AUC24-based strategies. Adequate documentation of sampling, correct storage and transport, accurate laboratory analysis, and pertinent data reporting are required to ensure appropriate interpretation of TDM data to guide vancomycin dosing recommendations. Ultimately, TDM data in the clinical context of the patient and their response to treatment should guide vancomycin therapy. Endorsed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology, the IATDMCT Anti-Infectives Committee, provides recommendations with respect to best clinical practice for vancomycin TDM.

Barriers and opportunities for the clinical implementation of therapeutic drug monitoring in oncology.

There are few fields of medicine in which the individualisation of medicines is more important than in the area of oncology. Under-dosing can have significant ramifications due to the potential for therapeutic failure and cancer progression; by contrast, over-dosing may lead to severe treatment-limiting side effects, such as agranulocytosis and neutropenia. Both circumstances lead to poor patient prognosis and contribute to the high mortality rates still seen in oncology. The concept of dose individualisation tailors dosing for each individual patient to ensure optimal drug exposure and best clinical outcomes. While the value of this strategy is well recognised, it has seen little translation to clinical application. However, it is important to recognise that the clinical setting of oncology is unlike that for which therapeutic drug monitoring (TDM) is currently the cornerstone of therapy (e.g. antimicrobials). Whilst there is much to learn from these established TDM settings, the challenges presented in the treatment of cancer must be considered to ensure the implementation of TDM in clinical practice. Recent advancements in a range of scientific disciplines have the capacity to address the current system limitations and significantly enhance the use of anticancer medicines to improve patient health. This review examines opportunities presented by these innovative scientific methodologies, specifically sampling strategies, bioanalytics and dosing decision support, to enable optimal practice and facilitate the clinical implementation of TDM in oncology.

The management of anti-infective agents in intensive care units: the potential role of a 'fast' pharmacology.

INTRODUCTION: Patients in intensive care units (ICU) are often developing severe infections in which are associated with significant mortality rates. A number of novel technologies for the rapid microbiological diagnosis of these infections have been developed, introducing the era of 'fast microbiology.' Treatment of bacterial and fungal infections in ICU is however complicated by alterations in the pharmacokinetics of antimicrobial agents. AREAS COVERED: We review novel pharmacologic tools that can be used to optimize anti-infective therapies and patient management in ICU. A MEDLINE Pubmed search for articles published from January 1995 to 2019 was completed matching the terms pharmacokinetics and pharmacology with antimicrobial agents and ICU or critically ill patients. Moreover, additional studies were identified from the reference list of retrieved articles. EXPERT OPINION: Several tools are in development for the full automation of the analytical methods used for the quantification of antimicrobial concentrations within a few hours after sample collection. Ad hoc software with adaptive feedback is also available for appropriate dose adjustments based on both individual patient covariate data and therapeutic drug monitoring (TDM) data when available. The application of these technological improvements in the clinical practice should open the way to a 'fast pharmacology' at the bedside.

Post Column Derivatization Using Reaction Flow High Performance Liquid Chromatography Columns.

A protocol for the use of reaction flow high performance liquid chromatography columns for methods employing post column derivatization (PCD) is presented. A major difficulty in adapting PCD to modern HPLC systems and columns is the need for large volume reaction coils that enable reagent mixing and then the derivatization reaction to take place. This large post column dead volume leads to band broadening, which results in a loss of observed separation efficiency and indeed detection in sensitivity. In reaction flow post column derivatization (RF-PCD) the derivatization reagent(s) are pumped against the flow of mobile phase into either one or two of the outer ports of the reaction flow column where it is mixed with column effluent inside a frit housed within the column end fitting. This technique allows for more efficient mixing of the column effluent and derivatization reagent(s) meaning that the volume of the reaction loops can be minimized or even eliminated altogether. It has been found that RF-PCD methods perform better than conventional PCD methods in terms of observed separation efficiency and signal to noise ratio. A further advantage of RF-PCD techniques is the ability to monitor effluent coming from the central port in its underivatized state. RF-PCD has currently been trialed on a relatively small range of post column reactions, however, there is currently no reason to suggest that RF-PCD could not be adapted to any existing one or two component (as long as both reagents are added at the same time) post column derivatization reaction.

Curtain Flow Column: Optimization of Efficiency and Sensitivity.

Active Flow Technology (AFT) is a form of column technology that increases the separation performance of a HPLC column through the use of a specially purpose built multiport end-fitting(s). Curtain Flow (CF) columns belong to the AFT suite of columns, specifically the CF column is designed so that the sample is injected into the radial central region of the bed and a curtain flow of mobile phase surrounding the injection of solute prevents the radial dispersion of the sample to the wall. The column functions as an 'infinite diameter' column. The purpose of the design is to overcome the radial heterogeneity of the column bed, and at the same time maximize the sample load into the radial central region of the column bed, which serves to increase detection sensitivity. The protocol described herein outlines the system and CF column set up and the tuning process for an optimized infinite diameter 'virtual' column.

A new approach to live reaction monitoring using active flow technology in ultra-high-speed HPLC with mass spectral detection.

A new type of chromatography column referred to as a parallel segmented flow (PSF) column enables ultra-high-speed high-performance liquid chromatography-MS to be undertaken. This occurs because the separation efficiency obtained on PSF columns has been shown in prior studies to be superior to conventional columns, and the flow stream is split radially inside the outlet end fitting of the column, rather than in an axial post-column flow stream split. As a result, the flow through the column can be five times higher than the flow through the MS. In this work, the degradation of amino acids in dilute nitric acid was used to illustrate the process. Separations were obtained in less than 12 s, although the reinjection process was initiated 6 s after the previous injection. The degradation rate constant of tryptophan, in the presence of tyrosine and phenylalanine, was determined.

Using active flow technology columns for high through-put and efficient analyses: The drive towards ultra-high through-put high-performance liquid chromatography with mass spectral detection.

The performance of active flow technology chromatography columns in parallel segmented flow mode packed with 5 µm Hypersil GOLD particles was compared to conventional UHPLC columns packed with 1.9 µm Hypersil GOLD particles. While the conventional UHPLC columns produced more theoretical plates at the optimum flow rate, when separations were performed at maximum through-put the larger particle size AFT column out-performed the UHPLC column. When both the AFT column and the UHPLC column were operated such that they yielded the same number of theoretical plates per separation, the separation on the AFT column was twice as fast as that on the UHPLC column, with the same level of sensitivity and at just 70% of the back pressure. Furthermore, as the flow velocity further increased the performance gain on the AFT column compared to the UHPLC column improved. An additional advantage of the AFT column was that the flow stream at the exit of the column was split in the radial cross section of the peak profile. This enables the AFT column to be coupled to a flow limiting detector, such as a mass spectrometer. When operated under high through-put conditions separations as fast as six seconds, using mobile phase flow rates in the order of 5-6 mL/min have been recorded.

Tuning a Parallel Segmented Flow Column and Enabling Multiplexed Detection.

Active flow technology (AFT) is new form of column technology that was designed to overcome flow heterogeneity to increase separation performance in terms of efficiency and sensitivity and to enable multiplexed detection. This form of AFT uses a parallel segmented flow (PSF) column. A PSF column outlet end-fitting consists of 2 or 4 ports, which can be multiplexed to connect up to 4 detectors. The PSF column not only allows a platform for multiplexed detection but also the combination of both destructive and non-destructive detectors, without additional dead volume tubing, simultaneously. The amount of flow through each port can also be adjusted through pressure management to suit the requirements of a specific detector(s). To achieve multiplexed detection using a PSF column there are a number of parameters which can be controlled to ensure optimal separation performance and quality of results; that is tube dimensions for each port, choice of port for each type of detector and flow adjustment. This protocol is intended to show how to use and tune a PSF column functioning in a multiplexed mode of detection.