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BACKGROUND: Voriconazole is an antifungal drug used for the treatment of invasive fungal infections. Due to highly variable drug exposure, therapeutic drug monitoring (TDM) has been recommended. TDM may be helpful to accurately predict exposure but covariates like severe inflammation influencing voriconazole metabolism have not been included in the population pharmacokinetic (popPK) models suitable for routine TDM.OBJECTIVES: The aim of this study was to investigate whether the effect of inflammation, reflected by C-reactive protein (CRP), could improve a popPK model that can be applied in clinical care.PATIENTS AND METHODS: Data from two previously conducted studies were included in the popPK modelling. PopPK modelling was performed using Edsim++. Different popPK models were compared by Akaike Information Criterion and goodness-of-fit plots.RESULTS: In total, 1060 voriconazole serum concentrations were included from 54 patients. The final model was a one-compartment model with nonlinear elimination. Only CRP was a significant covariate and was included in the final model and affected the maximum rate of enzyme activity (V max). For the final popPK model mean volume of distribution (Vd) was 145 L (CV%=61%), mean Michaelis-Menten constant (Km) was 5.7 mg/L (CV%=119%), mean V max was 86.4 mg/h (CV%=99%) and mean bioavailability (F) was 0.83 (CV%=143%). Internal validation using bootstrapping resulted in median values close to the population parameter estimates. CONCLUSIONS: This one compartment model with nonlinear elimination and CRP as a covariate adequately described voriconazole pharmacokinetics.

Non-contrast computed tomography (CT) scanning allows for reliable coronary calcium score (CCS) calculation at a low radiation dose and has been well established as marker to assess the future risk of coronary artery disease (CAD) events in asymptomatic individuals. However, the diagnostic and prognostic value in symptomatic patients remains a matter of debate. This narrative review focuses on the available evidence for CCS in patients with stable chest pain complaints.PubMed, Embase, and Web of Science were searched for literature using search terms related to three overarching categories: CT, symptomatic chest pain patients, and coronary calcium. The search resulted in 42 articles fulfilling the inclusion and exclusion criteria: 27 articles (n = 38 137 patients) focused on diagnostic value and 23 articles (n = 44 683 patients) on prognostic value of CCS. Of these, 10 articles (n = 21 208 patients) focused on both the diagnostic and prognostic value of CCS.Between 22 and 10 037 patients were included in the studies on the diagnostic and prognostic value of CCS, including 43 % and 51 % patients with CCS 0. The most evidence is available for patients with a low and intermediate pre-test probability (PTP) of CAD. Overall, the prevalence of obstructive CAD (OCAD, defined as a luminal stenosis of ≥ 50 % in any of the coronary arteries) as determined with CT coronary angiography in CCS 0 patients, was 4.4 % (n = 703/16 074) with a range of 0-26 % in individual studies. The event rate for major adverse cardiac events (MACE) ranged from 0 % to 2.1 % during a follow-up of 1.6 to 6.8 years, resulting in a high negative predictive value for MACE between 98 % and 100 % in CCS 0 patients. At increasing CCS, the OCAD probability and MACE risk increased. OCAD was present in 58.3 % (n = 617/1058) of CCS 400 patients with percentages ranging from 20 % to 94 % and MACE occurred in 16.7 % (n = 175/1048) of these patients with percentages ranging from 6.9 % to 50 %.Accumulating evidence shows that OCAD is unlikely and the MACE risk is very low in symptomatic patients with CCS 0, especially in those with low and intermediate PTPs. This suggests a role of CCS as a gatekeeper for additional diagnostic testing. Increasing CCS is related to an increasing probability of OCAD and risk of cardiac events. Additional research is needed to assess the value of CCS in women and patient management in a primary healthcare setting.· A CCS of zero makes OCAD in patients at low-intermediate PTP unlikely. · A CCS of zero is related to a very low risk of MACE. · Categories of increasing CCS are related to increasing rates of OCAD and MACE. · Future studies should focus on the diagnostic and prognostic value of CCS in symptomatic women and the role in primary care.· Koopman MY, Willemsen RT, van der Harst P et al. The Diagnostic and Prognostic Value of Coronary Calcium Scoring in Stable Chest Pain Patients: A Narrative Review. Fortschr Röntgenstr 2022; 194: 257 - 265.Die kontrastfreie Computertomografie (CT) ermöglicht eine zuverlässige Berechnung des koronaren Kalziumscores (KKS) bei niedriger Strahlendosis und hat sich als Marker zur Beurteilung des Risikos für koronare Herzkrankheiten (KHK) bei asymptomatischen Personen bewährt. Der diagnostische und prognostische Wert bei symptomatischen Patienten bleibt jedoch umstritten. Die vorliegende Übersichtsarbeit befasst sich mit der verfügbaren Evidenz des KKS bei Patienten mit stabilen Brustschmerzbeschwerden.In PubMed, Embase und Web of Science wurde eine Literaturrecherche mit Suchbegriffen zu drei übergeordneten Kategorien durchgeführt: CT, Patienten mit symptomatischen Brustschmerzen und Koronarkalk. Die Suche ergab 42 Artikel, die die Ein- und Ausschlusskriterien erfüllten: 27 Artikel (n = 38 137 Patienten) konzentrierten sich auf den diagnostischen Wert und 23 Artikel (n = 44 683 Patienten) auf den prognostischen Wert des KKS. Davon befassten sich 10 Artikel (n = 21 208 Patienten) mit dem diagnostischen und dem prognostischen Wert des KKS.In die Studien zum diagnostischen und prognostischen Wert des KKS wurden zwischen 22 und 10 037 Patienten eingeschlossen, darunter 43 % bzw. 51 % Patienten mit KKS0. Die meisten Erkenntnisse liegen für Patienten mit einer niedrigen und mittleren Prätestwahrscheinlichkeit (PTP) für KHK vor. Insgesamt lag die Prävalenz der obstruktiven KHK (OKHK, definiert als luminale Stenose von ≥ 50 % in einer der Koronararterien), die mittels CT-Koronarangiografie bei KKS0-Patienten bestimmt wurde, bei 4,4 % (n = 703/16 074) mit einem Bereich von 0–26 % in einzelnen Studien. Die Ereignisrate für schwerwiegende unerwünschte kardiale Ereignisse („major adverse cardiac events“ MACE) reichte von 0 % bis 2,1 % während einer Nachbeobachtungszeit von 1,6 bis 6,8 Jahren, was bei KKS 0-Patienten zu einem hohen negativen Vorhersagewert für MACE zwischen 98 % und 100 % führte. Mit zunehmendem KKS stiegen die OKHK-Wahrscheinlichkeit und das MACE-Risiko. Bei 58,3 % (n = 617/1058) der Patienten mit einem KKS 400 lag eine OKHK vor, wobei die Spanne von 20 % bis 94 % reichte. Bei 16,7 % (n = 175/1048) dieser Patienten trat ein MACE auf, mit einer Spanne von 6,9 % bis 50 %.Es gibt zunehmend mehr Hinweise darauf, dass bei symptomatischen Patienten mit KKS0 eine OKHK unwahrscheinlich und das MACE-Risiko sehr gering ist, insbesondere bei den Patienten mit niedriger und mittlerer PTP. Dies weist auf eine „Torwächter“-Rolle des KKS hinsichtlich zusätzlicher diagnostischer Tests hin. Mit zunehmendem KKS steigt sowohl die Wahrscheinlichkeit einer OKHK als das Risiko für kardiale Ereignisse. Weitere Forschungsarbeiten sind erforderlich, um den Wert des KKS bei Frauen und beim Patientenmanagement im Rahmen der medizinischen Grundversorgung zu bewerten.

Background Cytomegalovirus (CMV) can cause severe disease, including rejection in transplant recipients. Ganciclovir and its oral prodrug valganciclovir have been used as first-line therapy for CMV disease in transplant recipients. The exposure targets of ganciclovir are not exactly known, and toxicity and resistance have interfered with ganciclovir therapy. Objectives To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ganciclovir in transplant recipients. Methods We used patient data from a previous observational study on ganciclovir therapeutic drug monitoring (TDM) in prophylaxis and therapy. The ganciclovir concentrations and CMV viral loads were determined during routine clinical care. The PK/PD population modelling and simulations were done with non-parametric methodology using the Pmetrics program. Results Eighty-five patients were included in the PK modelling. The final PK model was a two-compartment model with first-order absorption and elimination. A subset of 17 patients on CMV therapy were included in the PD modelling. A median of 4 (range 2–8) viral loads were obtained per patient. A simulation of 10 000 patients showed that an approximately 1 log10 reduction of CMV viral load will be observed after 12.5 days at the current recommended dose. Conclusions The developed linked PK/PD population model and subsequent PD simulations showed slow decline of CMV viral load and it appears that dosing of (val)ganciclovir in this study might have been inadequate to achieve fast reduction of viral load. It is clear that further studies are needed to specify the PD effects of ganciclovir by performing systematic measurements of both ganciclovir concentrations and CMV viral loads.

Purpose Reduced exposure to echinocandins has been reported in specific patient populations, such as critically ill patients; however, fixed dosing strategies are still employed. The present review examines the accumulated evidence supporting echinocandin therapeutic drug monitoring (TDM) and summarizes available assays and sampling strategies. Methods A literature search was conducted using PubMed® in December 2020, with search terms such as echinocandins, anidulafungin, caspofungin, micafungin, or rezafungin with pharmacology, pharmacokinetics, pharmacodynamics, drug-drug interactions, therapeutic drug monitoring, resistance, drug susceptibility testing, toxicity, adverse drug reactions, bioanalysis, chromatography, and mass spectrometry. Data on pharmacokinetic/pharmacodynamic (PK/PD) outcome markers, drug resistance, PK variability, drug-drug interactions, assays, and TDM sampling strategies were summarized. Results Echinocandins demonstrate drug exposure-efficacy relationships, and maximum concentration/minimal inhibitory concentration ratio (Cmax/MIC) and area under the concentration-time curve/MIC ratio (AUC/MIC) are proposed PK/PD markers for clinical response. The relationship between drug exposure and toxicity remains poorly clarified. TDM could be valuable in patients at risk of low drug exposure, such as those with critical illness and/or obesity. TDM of echinocandins may also be useful in patients with moderate liver impairment, drug-drug interactions, hypoalbuminemia, and those undergoing extracorporeal membrane oxygenation, as these conditions are associated with altered exposure to caspofungin and/or micafungin. Assays are available to measure anidulafungin, micafungin, and caspofungin concentrations. A limited-sampling strategy for anidulafungin has been reported. Conclusion Echinocandin TDM should be considered in patients at known risk of suboptimal drug exposure. However, for implementing TDM, clinical validation of PK/PD targets is needed.

BACKGROUND: Therapeutic drug monitoring (TDM) supports personalized treatment. For successful implementation, TDM must have a turnaround time suited to the clinical needs of patients and their health care settings. Here, the authors share their views of how a TDM strategy can be tailored to specific settings and patient groups.METHODS: The authors selected distinct scenarios for TDM: high-risk, complex, and/or critically ill patient population; outpatients; and settings with limited laboratory resources. In addition to the TDM scenario approach, they explored potential issues with the legal framework governing dose escalation.RESULTS: The most important issues identified in the different scenarios are that critically ill patients require rapid turnaround time, outpatients require an easy sampling procedure for the sample matrix and sample collection times, settings with limited laboratory resources necessitate setting-specific analytic techniques, and all scenarios warrant a legal framework to capture the use of escalated dosages, ideally with the use of trackable dosing software.CONCLUSIONS: To benefit patients, TDM strategies need to be tailored to the intended population. Strategies can be adapted for rapid turnaround time for critically ill patients, convenient sampling for outpatients, and feasibility for those in settings with limited laboratory resources.

Nitric oxide is a gas produced in the airways of asthmatic subjects and related to T2 inflammation. It can be measured as fractional nitric oxide (FeNO) in the exhaled air and used as a non-invasive, easy to evaluate, rapid marker. It is now widely used in many settings to determine airway inflammation. The aim of this narrative review is to report relationship between FeNO and the physiopathologic characteristics of asthmatic patients. Factors affecting FeNO levels have also been analysed as well as the impact of corticosteroid, target therapies and rehabilitation programs. Considering the availability of the test, spreading this method-ology to low income countries has also been considered as a possibility for evaluating airway inflammation and monitoring adherence to inhaled corticosteroid therapy. PubMed data search has been performed restricted to English language papers. Research was limited to studies in adults unless studies in children were the only ones reported for a particular issue. This revision could be useful to summarize the role of FeNO in relation to asthma charac-teristics and help in the use of FeNO in different clinical settings particularly in low income countries. (c) 2020 Sociedade Portuguesa de Pneumologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contains fulltext : 292330.pdf (Publisher’s version ) (Open Access) The aim of this study was to evaluate the difference in drug exposure of rifampicin in native versus non-native Paraguayan populations using dried blood spots (DBS) samples collected utilizing a limited sampling strategy. This was a prospective pharmacokinetic study that enrolled hospitalized tuberculosis (TB) patients from both native and non-native populations receiving oral rifampicin 10 mg/kg once-daily dosing. Steady-state DBS samples were collected at 2, 4, and 6 h after intake of rifampicin. The area under the time concentration curve 0-24 h (AUC(0-24)) was calculated using a Bayesian population PK model. Rifampicin AUC(0-24) < 38.7 mg*h/L was considered as low. The probability of target attainment (PTA) was calculated using AUC(0-24)/MIC > 271 as a target and estimated MIC values of 0.125 and 0.25 mg/L. In total, 50 patients were included. Native patients (n = 30) showed comparable drug exposure to the non-natives (n = 20), median AUC(0-24) 24.7 (17.1-29.5 IQR) and 21.6 (15.0-35.4 IQR) mg*h/L (p = 0.66), respectively. Among total patients, only 16% (n = 8) had a rifampicin AUC(0-24) > 38.7 mg*h/L. Furthermore, PTA analysis showed that only 12 (24%) of the patients met a target AUC(0-24) /MIC ≥ 271, assuming an MIC of 0.125 mg/L, which plummeted to 0% at a wild-type MIC of 0.25 mg/L. We successfully used DBS and limited sampling for the AUC(0-24) estimation of rifampicin. Currently, our group, the EUSAT-RCS consortium, is preparing a prospective multinational, multicenter phase IIb clinical trial evaluating the safety and efficacy of high-dose rifampicin (35 mg/kg) in adult subjects using the DBS technique for AUC(0-24) estimation.

BackgroundSuboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.MethodsWe systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24andCmaxwere assessed with linear mixed-effects models.ResultsOf 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially 0–24for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24for isoniazid and pyrazinamide.N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24and slow acetylators had higher isoniazid AUC0–24than intermediate acetylators. Determinants ofCmaxwere generally similar to those for AUC0–24.ConclusionsThis study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

BACKGROUND: Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of Cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such as myelosuppression, which often leads to therapy cessation. Underdosing, as an attempt to prevent side effects, can lead to drug resistance and therapy failure. Therapeutic drug monitoring (TDM) has been used to overcome these problems. The purpose of this narrative review was to give an overview of ganciclovir TDM, available assays, population pharmacokinetic models, and discuss the current knowledge gaps. METHODS: For this narrative review, a nonsystematic literature search was performed on the PubMed database in April 2021. The following search terms were used: ganciclovir, valganciclovir, pharmacokinetics, pharmacodynamics, population pharmacokinetics, therapeutic drug monitoring, bioassay, liquid chromatography coupled with tandem mass spectrometry, liquid chromatography, chromatography, spectrophotometry, and toxicity. In addition, the reference lists of the included articles were screened. RESULTS: The most common bioanalysis method identified was liquid chromatography coupled with tandem mass spectrometry. There are different models presenting ganciclovir IC50; however, establishing a pharmacokinetic/pharmacodynamic target for ganciclovir based on preclinical data is difficult because there are no studies combining dynamic drug exposure in relation to inhibition of viral replication. The data on ganciclovir TDM show large interindividual variability, indicating that TDM may play a role in modifying the dose to reduce toxicity and prevent treatment failure related to low concentrations. The main hurdle for implementing TDM is the lack of robust data to define a therapeutic window. CONCLUSIONS: Although the pharmacokinetics (PK) involved is relatively well-described, both the pharmacodynamics (PD) and pharmacokinetic/pharmacodynamic relationship are not. This is because the studies conducted to date have mainly focused on estimating ganciclovir exposure, and owing to the limited therapeutic options for CMV infections, future studies on ganciclovir are warranted. ispartof: THERAPEUTIC DRUG MONITORING vol:44 issue:1 pages:138-147 ispartof: location:United States status: published

There has been an increased interest in pharmacokinetics and pharmacodynamics (PKPD) of anti-tuberculosis drugs. A better understanding of the relationship between drug exposure, antimicrobial kill and acquired drug resistance is essential not only to optimize current treatment regimens but also to design appropriately dosed regimens with new anti-tuberculosis drugs. Although the interest in PKPD has resulted in an increased number of studies, the actual bench-to-bedside translation is somewhat limited. One of the reasons could be differences in methodologies and outcome assessments that makes it difficult to compare the studies. In this paper we summarize most relevant in vitro, in vivo, in silico and human PKPD studies performed to optimize the drug dose and regimens for treatment of tuberculosis. The in vitro assessment focuses on MIC determination, static time-kill kinetics, and dynamic hollow fibre infection models to investigate acquisition of resistance and killing of Mycobacterium tuberculosis populations in various metabolic states. The in vivo assessment focuses on the various animal models, routes of infection, PK at the site of infection, PD read-outs, biomarkers and differences in treatment outcome evaluation (relapse and death). For human PKPD we focus on early bactericidal activity studies and inclusion of PK and therapeutic drug monitoring in clinical trials. Modelling and simulation approaches that are used to evaluate and link the different data types will be discussed. We also describe the concept of different studies, study design, importance of uniform reporting including microbiological and clinical outcome assessments, and modelling approaches. We aim to encourage researchers to consider methods of assessing and reporting PKPD of anti-tuberculosis drugs when designing studies. This will improve appropriate comparison between studies and accelerate the progress in the field.

There has been an increased interest in pharmacokinetics and pharmacodynamics (PKPD) of anti-tuberculosis drugs. A better understanding of the relationship between drug exposure, antimicrobial kill and acquired drug resistance is essential not only to optimize current treatment regimens but also to design appropriately dosed regimens with new anti-tuberculosis drugs. Although the interest in PKPD has resulted in an increased number of studies, the actual bench-to-bedside translation is somewhat limited. One of the reasons could be differences in methodologies and outcome assessments that makes it difficult to compare the studies. In this paper we summarize most relevant

Refereed/Peer-reviewed 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.

BackgroundSELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset spine rigidity and respiratory insufficiency. A muscular dystrophy caused by mutations in theLAMA2gene (LAMA2-related muscular dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe, early-onset due to complete Laminin subunit α2 deficiency (merosin-deficient congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or adult-onset due to partial Laminin subunit α2 deficiency. For both muscle diseases, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data and appropriate clinical and functional outcome measures are needed to reach trial readiness.MethodsLAST STRONG is a natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM or LAMA2-MD, starting August 2020. Patients have four visits at our hospital over a period of 1.5 year. At all visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, questionnaires (patient report and/or parent proxy; age ≥ 2 years), muscle ultrasound including diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), and accelerometry for 8 days (age ≥ 2 years); at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography; age ≥ 2 years), spine X-ray (age ≥ 2 years), dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years) and full body magnetic resonance imaging (MRI) (age ≥ 10 years). All examinations are adapted to the patient’s age and functional abilities. Correlation between key parameters within and between subsequent visits will be assessed.DiscussionOur study will describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD, enabling us to select relevant clinical and functional outcome measures for reaching clinical trial-readiness. Moreover, our detailed description (deep phenotyping) of the clinical features will optimize clinical management and will establish a well-characterized baseline cohort for prospective follow-up.ConclusionOur natural history study is an essential step for reaching trial readiness in SELENON-RM and LAMA2-MD.Trial registrationThis study has been approved by medical ethical reviewing committee Region Arnhem-Nijmegen (NL64269.091.17, 2017–3911) and is registered atClinicalTrial.gov(NCT04478981).

The purpose of the study was to assess the status of emerging therapeutic drug monitoring (TDM) of anti-infective agents in Australian hospitals. A nationwide cross-sectional survey of all Australian hospitals operating in the public and private health sector was conducted between August and September 2019. The survey consisted of questions regarding institutional TDM practice for anti-infective agents and clinical vignettes specific to β-lactam antibiotics. Responses were received from 82 unique institutions, representing all Australian states and territories. All 29 (100%) of principal referral (major) hospitals in Australia participated. Five surveys were partially complete. Only 25% (20/80) of hospitals had TDM testing available on-site for any of the eight emerging TDM candidates considered: β-lactam antibiotics, anti-tuberculous agents, flucytosine, fluoroquinolones, ganciclovir, human immunodeficiency virus (HIV) drugs, linezolid and teicoplanin. A considerable time lag was noted between TDM sampling and reporting of results. With respect to β-lactam antibiotic TDM, variable indications, pharmacodynamic targets and sampling times were identified. The three greatest barriers to local TDM performance were found to be (1) lack of timely assays/results, (2) lack of institutional-wide expertise and/or training and (3) lack of guidelines to inform ordering of TDM and interpretation of results. The majority of respondents favoured establishing national TDM guidelines and increasing access to dose prediction software, at rates of 89% and 96%, respectively. Translating emerging TDM evidence into daily clinical practice is slow. Concerted efforts are required to address the barriers identified and facilitate the implementation of standardised practice.

Pyrazinamide is one of the first-line antituberculosis drugs. The efficacy of pyrazinamide is associated with the ratio of 24-h area under the concentration–time curve (AUC(24)) to MIC. The objective of this study was to develop and validate a limited sampling strategy (LSS) based on a population pharmacokinetic (popPK) model to predict AUC(24). A popPK model was developed using an iterative two-stage Bayesian procedure and was externally validated. Using data from 20 treatment-naive adult tuberculosis (TB) patients, a one compartment model with transit absorption and first-order elimination best described pyrazinamide pharmacokinetics and fed state was the only significant covariate for absorption rate constant (k(a)). External validation, using data from 26 TB patients, showed that the popPK model predicted AUC(24) with a slight underestimation of 2.1%. LSS were calculated using Monte Carlo simulation (n = 10,000). External validation showed LSS with time points 0 h, 2 h, and 6 h performed best with RMSE of 9.90% and bias of 0.06%. Food slowed absorption of pyrazinamide, but did not affect bioavailability, which may be advantageous in case of nausea or vomiting in which food can be used to diminish these effects. In this study, we successfully developed and validated a popPK model and LSS, using 0 h, 2 h, and 6 h postdose samples, that could be used to perform therapeutic drug monitoring (TDM) of pyrazinamide in TB patients.

OBJECTIVES It is recommended that therapeutic monitoring of vancomycin should be guided by 24-hour area under the curve concentration. This can be done via Bayesian models in dose-optimization software. However, before these models can be incorporated into clinical practice in the critically ill, their predictive performance needs to be evaluated. This study assesses the predictive performance of Bayesian models for vancomycin in the critically ill. DESIGN Retrospective cohort study. SETTING Single-center ICU. PATIENTS Data were obtained for all patients in the ICU between 1 January, and 31 May 2020, who received IV vancomycin. The predictive performance of three Bayesian models were evaluated based on their availability in commercially available software. Predictive performance was assessed via bias and precision. Bias was measured as the mean difference between observed and predicted vancomycin concentrations. Precision was measured as the sd of bias, root mean square error, and 95% limits of agreement based on Bland-Altman plots. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A total of 466 concentrations from 188 patients were used to evaluate the three models. All models showed low bias (-1.7 to 1.8 mg/L), which was lower with a posteriori estimate (-0.7 to 1.8 mg/L). However, all three models showed low precision in terms of sd (4.7-8.8 mg/L) and root mean square error (4.8-8.9 mg/L). The models underpredicted at higher observed vancomycin concentrations (bias 0.7-3.2 mg/L for < 20 mg/L; -5.1 to -2.3 for ≥ 20 mg/L) and the Bland-Altman plots showed a great deviation between observed and predicted concentrations. CONCLUSIONS Bayesian models of vancomycin show not only low bias, but also low precision in the critically ill. Thus, Bayesian-guided dosing of vancomycin in this population should be used cautiously.