Ana Martín-Suárez

Vancomycin dosing assessment in intensive care unit patients based on a population pharmacokinetic/pharmacodynamic simulation

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Despite the frequent use of vancomycin in intensive care unit (ICU) patients, few studies aimed at characterizing vancomycin population pharmacokinetics have been performed in this critical population. * Population pharmacokinetics coupled with pharmacodynamic analysis, in order to optimize drug exposure and hence antibacterial effectiveness, has been little applied in these specific patients. WHAT THIS STUDY ADDS * Our population model characterized the pharmacokinetic profile of vancomycin in adult ICU patients, higher distribution volume values (V) being observed when the patients serum creatinine (Cr(Se)) was greater than 1 mg dl(-1). * Age and creatinine clearance (CL(cr)) were identified as the main covariates explaining the pharmacokinetic variability in vancomycin CL. * Our pharmacokinetic/pharmacodynamic (PK/PD) simulation should aid clinicians to select initial vancomycin doses that will maximize the rate of response in the ICU setting, taking into account the patients age and renal function as well as the susceptibility of Staphylococcus aureus. AIM To estimate the vancomycin pharmacokinetic profile in adult ICU patients and to assess vancomycin dosages for increasing the likelihood of optimal exposure. METHODS Five hundred and sixty-nine concentration-time data from 191 patients were analysed using a population pharmacokinetic approach (NONMEN). External model evaluation was made in 46 additional patients. The 24 h area under the concentration-time curve (AUC(0,24 h)) was derived from the final model. Minimum inhibitory concentration (MIC) values for S. aureus were obtained from the EUCAST database. AUC(0,24 h) : MIC >/= 400 was considered as PK/PD efficacy index. The probability of different dosages attaining the target considering different strains of S. aureus and patient subgroups was estimated with Monte Carlo simulation. RESULTS Vancomycin CL showed a significant dependence on patient age and renal function whereas Cr(Se) > 1 mg dl(-1) increased V more than twofold. For our representative ICU patient, 61 years, 73 kg, Cr(Se)= 1.4 mg dl(-1), measured CL(Cr)= 74.7 ml min(-1), the estimated values were CL = 1.06 ml min(-1) kg(-1) and V= 2.04 l kg(-1). The cumulative fraction of response for a standard vancomycin dose (2 g day(-1)) was less than 25% for VISA strains, and 33% to 95% for susceptible S. aureus, depending on patient characteristics. CONCLUSIONS Simulations provide useful information regarding the initial assessment of vancomycin dosing, the conventional dosing regimen probably being suboptimal in adult ICU patients. A graphic approach provides the recommended dose for any selected probability of attaining the PK/PD efficacy target or to evaluate the cumulative fraction of response for any dosing regimen in this population.

Monitoring and feedback of learning processes in virtual worlds through analytics architectures: A real case

The application of techniques related to Learning Analytics, including the recovery and processing of data and evidences related with the learning tasks, might result capital to improve educational processes that occurs within the virtual worlds. This paper aims to show a real example of application of a learning analytics framework which supports a real case of practical learning in a 3D virtual environment, analyzing in depth the problems that arises there from. As remarkable outcomes, this paper shows a whole system that comprises several tools, which make possible the automatization of a learning process inside a virtual world with the subject of quality assurance in pharmacy laboratories.

Usalpharma: a cloud-based architecture to support quality assurance training processes in health area using virtual worlds.

This paper discusses how cloud-based architectures can extend and enhance the functionality of the training environments based on virtual worlds and how, from this cloud perspective, we can provide support to analysis of training processes in the area of health, specifically in the field of training processes in quality assurance for pharmaceutical laboratories, presenting a tool for data retrieval and analysis that allows facing the knowledge discovery in the happenings inside the virtual worlds.

Modification of the EMIT immunoassay for the measurement of unbound mycophenolic acid in plasma

OBJECTIVES Evaluation of the performance of a modified Enzyme Multiplied Immunoassay Technique for therapeutic drug monitoring of plasma free mycophenolic acid (fMPA) concentrations. DESIGN AND METHODS A fMPA assay was developed on a Viva-E analyzer. A study of prior ultrafiltration conditions and analytical validation of the EMIT assay were performed. RESULTS The method was reliable and reproducible. CONCLUSIONS fMPA levels can be monitored using this EMIT assay with the advantage of being an automated method.

Evaluating amikacin dosage regimens in intensive care unit patients: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

The objectives of this study were to conduct a comparative pharmacokinetic/pharmacodynamic (PK/PD) evaluation using Monte Carlo simulation of conventional versus high-dose extended-interval dosage (HDED) regimens of amikacin (AMK) in intensive care unit (ICU) patients for an Acinetobacter baumannii infection model. The simulation was performed in five populations (a control population and four subpopulations of ICU patients). Using a specific AMK PK/PD model and Monte Carlo simulation, the following were generated: simulated AMK steady-state plasma level curves; PK/PD efficacy indexes [time during which the serum drug concentration remains above the minimum inhibitory concentration (MIC) for a dosing period (%T>MIC) and ratio of peak serum concentration to MIC (Cmax/MIC)]; evolution of bacterial growth curves; and adaptive resistance to treatment. A higher probability of bacterial resistance was observed with the HDED regimen compared with the conventional dosage regimen. A statistically significant increase in Cmax/MIC and a statistically significant reduction in %T>MIC with the HDED regimen were obtained. A multiple linear relationship between CFU values at 24h with Cmax/MIC and %T>MIC was obtained. In conclusion, with the infection model tested, the likelihood of resistance to treatment may be higher against pathogens with a high MIC with the HDED regimen, considering that in many ICU patients the %T>MIC may be limited. If a sufficient value of %T>MIC (≥60%) is not reached, even though the Cmax/MIC is high, the therapeutic efficacy of the treatment may not be guaranteed. This study indicates that different AMK dosing strategies could directly influence the efficacy results in ICU patients.

Approaches for dosage individualisation in critically ill patients

Introduction: Pharmacokinetic variability in critically ill patients is the result of the overlapping of multiple pathophysiological and clinical factors. Unpredictable exposure from standard dosage regimens may influence the outcome of treatment. Therefore, strategies for dosage individualisation are recommended in this setting. Areas covered: The authors focus on several approaches for dosage individualisation that have been developed, ranging from the well-established therapeutic drug monitoring (TDM) up to the innovative application of pharmacogenomics criteria. Furthermore, the authors summarise the specific population pharmacokinetic models for different drugs developed for critically ill patients to improve the initial dosage selection and the Bayesian forecasting of serum concentrations. The authors also consider the use of Monte Carlo simulation for the selection of dosage strategies. Expert opinion: Pharmacokinetic/pharmacodynamics (PK/PD) modelling and dosage individualisation methods based on mathematical and statistical criteria will contribute in improving pharmacologic treatment in critically ill patients. Moreover, substantial effort will be necessary to integrate pharmacogenomics criteria into critical care practice. The lack of availability of target biomarkers for dosage adjustment emphasizes the value of TDM which allows a large part of treatment outcome variability to be controlled.

Using software architectures to retrieve interaction information in eLearning environments

This research paper presents a software architecture based on services and deployed in a cloud environment that retrieves, analyzes and presents information collected from a closed eLearning environment like the Virtual Worlds. This software architecture is able to gather the user interaction in the digital platform, organize the interaction data and to perform measurements, estimates and basic analysis of the data, in order to give information to the managers and teachers about usage indicators and the resolution degree of the goals that students need to achieve in these scenarios and learning systems. To test this idea, the paper describe the application of the analytics layer of this software architecture on a real case, so it is possible to understand how can help this kind of architectures in the detection of the achievement of the learning goals or in the knowledge discover about users usage within the learning environment.

Clinical Repercussions of Analytical Interferences Due to Aldosterone Antagonists in Digoxin Immunoassays: An Assessment

Analytical interferences in digoxin immunoassays constitute a well-known problem, with repercussions for therapeutic drug monitoring. Clinically effective doses of spironolactone and potassium canrenoate cross-react in several digoxin immunoassays, producing falsely elevated or lowered concentrations. This study evaluates the interferences caused by these drugs in the microparticle enzyme immunoassay (MEIA III) in comparison with another 3 immunoassays used for digoxin therapeutic drug monitoring: MEIA II, fluorescence polarization immunoassay, and enzyme multiplied immunoassay. The potential clinical implications of assay discrepancies in patient care are also assessed. To evaluate assay performance, in vitro specimens and real patient samples were measured using the 4 assays. Five serum pools were spiked with digoxin to achieve concentrations of 1 and 2.25 ng/mL digoxin and measured with the immunoassays before and after supplementation. Real samples from patients receiving digoxin (n = 39), digoxin and spironolactone (n = 35), or digoxin and potassium canrenoate (n = 4) were also quantified. The influence of ultrafiltration was evaluated in 3 pools from 29 additional patients. The implications of assay discrepancies for dose recommendations were also evaluated. In general, the results obtained for the in vitro and in vivo approaches coincided, confirming statistically significant differences in the assays regardless of the type of sample. MEIA III showed positive interference against the well-known negative interference attributed to MEIA II. According to Bland-Altman analysis, it is not possible to assume the interchangeability of the immunoassays evaluated. Thus, individual patients must be monitored with the same technique even in the absence of potential interferences. Discordant digoxin dose recommendations were estimated in 31% of patients not treated with interfering drugs and in 43% of cotreated patients. From a clinical perspective, analytical interferences in digoxin immunoassays are a real and frequent problem, which seems even more important in view of the lower therapeutic range now recommended.

Pharmacokinetics and dosing requirements of digoxin in pregnant women treated for fetal supraventricular tachycardia

ABSTRACT Background: The objective of this study was to characterize the pharmacokinetics (PK) of digoxin in pregnant women and its potential implications for drug dosing. Methods: Serum digoxin concentrations (SDCs) obtained in pregnant women treated for fetal supraventricular tachycardia (SVT) was retrospectively collected. PK analysis was comparatively performed using a two-stage approach (PKS™) and a Population PK approach (NONMEM™). As clinical outcome the fetal heart rate was recorded. Results: A total of 42 SDCs were obtained from 8 women in the 3rd trimester of pregnancy (mean age 33.0 years). The PK parameters estimated by both two-stage (volume of distribution (Vd) = 682.0 L, CV = 47.5%; serum clearance (CL) = 16.1 L/h, CV = 19%) and population approaches (Vd = 731.3 L, CV = 30.5%; CL = 18.7 L/h, CV = 17.8%) are very similar and show a clear trend of increasing drug disposition in the third trimester of pregnancy. An oral loading dose of 0.5 mg/8 h during 24 h followed by a maintenance regimen of 0.5 mg/12 h been recommended to start treatment. Conclusions: Despite the small population, these parameters could be used as a guide to calculate the initial dosage requirements in the third trimester of pregnancy for treating fetal SVT. In addition, maternal SDCs should be routinely monitored for dosage adjustment purposes.

Therapeutic drug monitoring of tumour necrosis factor inhibitors in the management of chronic inflammatory diseases

Tumour necrosis factor inhibitor therapy has drastically changed the management of chronic inflammatory diseases. Some important drawbacks that can cause loss of response during treatment with these drugs are related to their large individual variability, the disease burden and the formation of antidrug antibodies that increase its clearance. Therapeutic drug monitoring of these drugs is not yet recommended by all scientific societies, and if so, only in patients with inflammatory symptoms. Proactive therapeutic drug monitoring represents a new strategy with many potential clinical benefits, including the prevention of immunogenicity, a reduction in the need for rescue therapy and greater durability of tumour necrosis factor inhibitor treatment. The review is based on a systematic search of the literature for controlled trials, systematic reviews, experimental studies, guideline papers and cohort studies addressing the best practice in tumour necrosis factor inhibitor therapeutic drug monitoring. Although there is ample evidence supporting the use of therapeutic drug monitoring in clinical practice to achieve better outcomes, some challenges have been detected. Many studies are focused on finding solutions for the lack of standardization of analytical methods to measure tumour necrosis factor inhibitor and antidrug antibodies concentrations. Other challenges are development of effective cost-saving proactive algorithms to identify optimal drug concentrations and the research on the role of antidrug antibodies, especially in the management and prevention of loss of response. Therapeutic drug monitoring of tumour necrosis factor inhibitor offers a rational approach to the optimization of the treatment of chronic inflammatory disease. Although prospective controlled trials yield little conclusive evidence of its benefits, there is growing acceptance of its value in clinical practice.