The objective of this study was to develop a population pharmacokinetic model for linezolid in hematooncological patients with sepsis, and to propose dosing optimization based on pharmacokinetic covariates that would lead to improved achievement of the PK/PD target. Therapeutic drug monitoring data from hematooncological patients treated with linezolid for suspected or proven sepsis were analyzed. A pharmacokinetic population model for linezolid was constructed using a nonlinear mixed-effects modeling approach. Monte Carlo simulations were then used to compare various dosing regimens in terms of PK/PD target attainment. A total of 197 linezolid serum concentrations obtained from 22 patients were included in the analysis. Patients' age was found to be the most predictive covariate for linezolid pharmacokinetics. In a patient with a median age of 59 years, the volume of distribution and clearance of linezolid were 46.2 L and 12.1 L/h, respectively. During the first 4 days of therapy, linezolid clearance decreased by 33%. The probability of PK/PD target attainment increased through the individualization of the dose according to the patient's age, administration of a loading dose, and administration of linezolid via continuous infusion. For this scenario, an easy-to-use nomogram was designed.

• Klíčová slova
• Monte Carlo simulation, PK/PD target, age, nonlinear mixed‐effects modeling, oxazolidinone, therapeutic drug monitoring,
• MeSH
• antibakteriální látky * farmakokinetika   aplikace a dávkování   MeSH
• biologické modely * MeSH
• dospělí MeSH
• grampozitivní bakteriální infekce * farmakoterapie   mikrobiologie   krev   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• linezolid * farmakokinetika   aplikace a dávkování   MeSH
• metoda Monte Carlo MeSH
• monitorování léčiv metody   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sepse * farmakoterapie   mikrobiologie   diagnóza   krev   MeSH
• věkové faktory MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky * MeSH
• linezolid * MeSH

BACKGROUND AND OBJECTIVES: Ustekinumab (USTE) and vedolizumab (VEDO) are increasingly used in paediatric patients with inflammatory bowel diseases (pIBD). However, data on the usefulness of therapeutic drug monitoring (TDM) in children are scarce. The primary objective of this study was to evaluate the association between disease activity, measured by faecal calprotectin (F-CPT), and serum trough levels (TLs) of USTE and VEDO. Secondary outcomes were to explore factors potentially associated with the outcome and exposure, to determine the optimal USTE or VEDO dose that predicts remission (defined as F-CPT < 250 µg/g), to validate our hypothesis using a proof-of-concept cohort (POCC) and to assess the occurrence of serum antibodies to USTE and VEDO. METHODS: This was a prospective single-centre observational study performed at the University Hospital Motol, Prague, Czech Republic. Of the 87 patients (51 Crohn's disease (CD), 30 ulcerative colitis (UC), and 6 IBD unclassified (IBD-U)), drug serum TLs and antibodies were measured in 282 observations (49 treatment courses) of USTE and 359 observations (38 courses) of VEDO. Serum and stool samples were collected before each study drug application during both the induction and maintenance phases of the treatment throughout the entire study period (January 2020 to June 2024). Clinical and laboratory data were obtained from the nationwide prospective registry CREdIT. Patients with perianal disease and those with previous major bowel surgery were not excluded from the study. As a POCC, we analysed a group of pIBD treated at our centre with anti-TNF agents-adalimumab or infliximab. RESULTS: In a linear multiple regression mixed model, an association was observed between logF-CPT levels and USTE treatment duration (β -0.0010, 95% confidence interval (CI) -0.0015 to -0.0006, p < 0.001) but not with USTE TLs (p = 0.12). VEDO TLs and logF-CPT levels were negatively associated both in the linear (β -0.0173, 95% CI -0.0292 to -0.0053, p = 0.005) and categorical models (p = 0.026), even after adjusting for time. A VEDO TL of 15.1 µg/mL showed the best, though still poor, combination of sensitivity (0.82) and specificity (0.32) to predict F-CPT < 250 µg/g (area under the curve (AUC) 0.56, 95% CI 0.49-0.63). Intensification, induction phase, undetectable TLs, and type of IBD (CD, UC, IBD-U) were not associated with logF-CPT. Slightly elevated anti-drug antibodies were detected in 5 USTE and 16 VEDO observations, with no clinical implications. CONCLUSIONS: TDM of USTE does not appear to be useful in pIBD. TDM of VEDO may assist in therapeutic strategy decisions, although establishing clinically useful cut-offs remains challenging.

• MeSH
• dítě MeSH
• feces * chemie   MeSH
• gastrointestinální látky * krev   terapeutické užití   farmakokinetika   MeSH
• humanizované monoklonální protilátky * krev   terapeutické užití   farmakokinetika   aplikace a dávkování   MeSH
• idiopatické střevní záněty * farmakoterapie   krev   MeSH
• leukocytární L1-antigenní komplex * analýza   metabolismus   MeSH
• lidé MeSH
• mladiství MeSH
• monitorování léčiv metody   MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• ustekinumab * krev   terapeutické užití   farmakokinetika   aplikace a dávkování   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Názvy látek
• gastrointestinální látky * MeSH
• humanizované monoklonální protilátky * MeSH
• leukocytární L1-antigenní komplex * MeSH
• ustekinumab * MeSH
• vedolizumab MeSH Prohlížeč

Epilepsy, affecting over 50 million people globally, presents a significant neurological challenge. Effective prevention of epileptic seizures relies on proper administration and monitoring of Anti-Seizure Medication (ASMs). Therapeutic Drug Monitoring (TDM) ensures optimal dosage adjustment, minimizing adverse effects and potential drug interactions. While traditional venous blood collection for TDM may be stressful, emerging alternative sampling methods, particularly Dried Blood Spot (DBS) or oral fluid offer less invasive way of sampling. This study aimed to develop and validate an analytical method for the determination of lamotrigine in such alternative samples. The sample, either DBS or oral fluid, was subjected to extraction, evaporation, and reconstitution in 15 % acetonitrile containing 0.1 % formic acid. A Kinetex C18 Polar column was used for liquid chromatographic separation and MS in ESI+ mode was used for detection and quantitation of lamotrigine using an isotopically labelled internal standard according to EMA guidelines. The calibration range of the developed method enables the determination of lamotrigine in the concentration range of 1-30 μg/mL in DBS and 0.5-20 μg/mL in oral fluid. Oral fluid and DBS samples from patients treated with lamotrigine analysed by the developed method were compared to plasma concentrations measured by the hospital's accredited laboratory. Preliminary results indicate a promising potential for these alternative matrices in clinical TDM applications. By offering a less invasive sampling approach, this method improves the accessibility and safety of pharmacotherapy for epilepsy patients. The results of this study lay the foundation for further clinical applications by implementing alternative matrix TDM, which may significantly advance personalized care in epilepsy management.

• Klíčová slova
• Alternative matrix, Antiepileptics, Dried blood spot, Lamotrigine, Quantification, Saliva, Validation,
• MeSH
• antikonvulziva * analýza   krev   MeSH
• chromatografie kapalinová metody   MeSH
• epilepsie farmakoterapie   MeSH
• kalibrace MeSH
• kapalinová chromatografie-hmotnostní spektrometrie MeSH
• lamotrigin * analýza   krev   MeSH
• lidé MeSH
• limita detekce MeSH
• monitorování léčiv * metody   MeSH
• reprodukovatelnost výsledků MeSH
• sliny * chemie   MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• test suché kapky krve * metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• validační studie MeSH
• Názvy látek
• antikonvulziva * MeSH
• lamotrigin * MeSH

Unfractionated heparin has long been considered the standard anticoagulation in ECMO, despite some pitfalls such as heparin resistance, heparin induced thrombocytopenia (HIT), etc Recently, some centres started to increasingly use argatroban for this purpose, typically using activated partial thromboplastin time (aPTT) for its monitoring. Direct monitoring of the efficacy of argatroban using Anti-IIa is not yet an established method, although it might be more appropriate as it targets the same pathway.An observational study was performed in adult veno-venous ECMO patients hospitalized with SARS-CoV-2 infection anticoagulated with argatroban to an aPTT target of 40-60 s and Anti-IIa target of 0.4-0.6 µg/mL. Bleeding and thrombotic complications were monitored.Forty-four VV ECMO patients were included, with an overall hospital mortality of approx. 50%. No life-threatening thrombotic events were recorded. The risk of bleeding complications significantly increased with aPTT above 52.7 s and with Anti-IIa values over 0.78 µg/mL. Using the above cut-offs for both the aPTT and Anti-IIa and their combination, the negative predictive value for bleeding was approximately 90%.It seems that the generally recommended limits for Anti-IIa of 1.5 µg/mL may be high. However, further data are needed to confirm lower limits.Trial Registration:retrospectively registered in ClinicalTrials.gov, NCT06038682.

• Klíčová slova
• Anti-IIa, activated partial thromboplastin time (aPTT), anticoagulation, argatroban, extracorporeal oxygenation (ECMO), monitoring,
• MeSH
• antikoagulancia * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• arginin analogy a deriváty   MeSH
• COVID-19 * krev   terapie   mortalita   komplikace   MeSH
• dospělí MeSH
• farmakoterapie COVID-19 * MeSH
• krvácení chemicky indukované   MeSH
• kyseliny pipekolové * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mimotělní membránová oxygenace * metody   MeSH
• monitorování léčiv metody   MeSH
• parciální tromboplastinový čas MeSH
• SARS-CoV-2 MeSH
• senioři MeSH
• sulfonamidy MeSH
• trombóza prevence a kontrola   etiologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Názvy látek
• antikoagulancia * MeSH
• argatroban MeSH Prohlížeč
• arginin MeSH
• kyseliny pipekolové * MeSH
• sulfonamidy MeSH

BACKGROUND: Schizophrenia is a serious mental illness, the pharmacological treatment of which comprises primarily the use of antipsychotics. However, non-adherence to their use and its reliable determination present a serious clinical and economic problem. This study aimed to determine therapeutic adherence in outpatients with schizophrenia spectrum disorders by combining short-term electronic monitoring of dispenser opening with the measurement of antipsychotic blood concentrations. METHODS: A total of 55 patients underwent a week-long electronic monitoring of dispenser opening and measurement of blood concentrations before and after monitoring. Patients who correctly opened the dispenser at least in 80% of scheduled time points during the weekly interval and, at the same time, did not show a change in blood concentration of the antipsychotic by more than 30% in any direction, were considered adherent. RESULTS: 69.1% of the patients met the adherence criteria, which was less than that determined by the Drug Attitude Inventory (DAI-10), the Visual Analogue Scale (VAS), and the Clinician Rating Scale (CRS). 7.3% of the patients took less than 80% of the prescribed doses and a change in blood concentrations of the antipsychotic by more than 30% was detected in 25.4% of the patients. In 70.9% of patients, the detected concentrations were within the recommended therapeutic reference interval. The groups of adherent and non-adherent patients did not differ statistically significantly in the severity of their illness as determined by the Clinical Global Impression (CGI), the Personal and Social Performance scale (PSP), and the Positive and Negative Syndrome Scale (PANSS). CONCLUSIONS: The combined method of evaluating adherence in schizophrenia patients confirmed the results determined by other methods. The benefits of this approach are described in the paper.

• Klíčová slova
• Antipsychotics, Schizophrenia, Telehealth, Therapeutic adherence, Therapeutic drug monitoring,
• MeSH
• adherence k farmakoterapii * psychologie   MeSH
• antipsychotika * krev   terapeutické užití   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• monitorování léčiv * metody   MeSH
• prospektivní studie MeSH
• schizofrenie * farmakoterapie   krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antipsychotika * MeSH

This study aimed to develop a vancomycin population pharmacokinetic model in obese adult patients treated with intermittent haemodialysis and propose a model-based loading dose strategy ensuring attainment of newly recommended AUC-based PK/PD target. Retrospective cross-sectional analysis was performed among obese haemodialysis dependent adult patients treated with intravenous vancomycin. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were used to identify the optimal loading dose for PK/PD target attainment during the first 48 h of treatment. Therapeutic drug monitoring data from 27 patients with a BMI of 30.2-52.9 kg/m2 were analysed. Among all tested variables, only LBM as a covariate of vancomycin Vd significantly improved the model, while vancomycin CL did not correlate with any of the tested variables. The median (IQR) value from the conditional mean of individual estimates of Vd and CL was 68.4 (56.6-84.2) L and 0.86 (0.79-0.90) L/h, respectively. To ensure optimal vancomycin exposure during the first 48 h of therapy, the vancomycin loading dose of 1500, 1750, 2000, 2250, 2500 and 2750 mg should be administered to obese patients with a lean body mass of ˂50, 50-60, 60-70, 70-80, 80-85 and >85 kg, respectively.

• Klíčová slova
• Chronic kidney disease, Monte Carlo simulation, acute kidney injury, lean body mass, nonlinear mixed-effects modelling, therapeutic drug monitoring,
• MeSH
• antibakteriální látky * farmakokinetika   aplikace a dávkování   MeSH
• biologické modely MeSH
• dialýza ledvin * metody   MeSH
• dospělí MeSH
• index tělesné hmotnosti MeSH
• lidé středního věku MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• monitorování léčiv metody   MeSH
• obezita * komplikace   metabolismus   MeSH
• plocha pod křivkou MeSH
• průřezové studie MeSH
• retrospektivní studie MeSH
• senioři MeSH
• vankomycin * farmakokinetika   aplikace a dávkování   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky * MeSH
• vankomycin * MeSH

Ocrelizumab is a second generation recombinant humanized IgG1 monoclonal antibody used for the treatment of multiple sclerosis that selectively target B cells expressing the CD20 antigen. This study aimed to develop and validate a UPLC-MS/MS method for quantification of ocrelizumab in human serum, which can be used in clinical applications for therapeutic drug monitoring. The analysis of ocrelizumab was performed using a bottom-up approach on a liquid chromatography coupled to tandem mass spectrometry detection. The method involved immunoglobulin precipitation with cold methanol followed by peptide digestion with trypsin. The resulting specific peptides were separated on an Acquity UPLC BEH C18 column at 55 °C using gradient elution. The method was validated according to European Medicines Agency (EMEA) guidelines and demonstrated intra- and inter-assay precision with coefficients of variation ranging from 1.6 % to 6.1 % and accuracies between 90.2 % and 107.2 %. Stability testing, including autosampler, long-term and freeze-thaw stability, showed no more than 15 % variation. The method was successfully applied to 169 patient samples, revealing ocrelizumab concentrations ranging from 0.5 to 21.8 mg/L in patients on 6-month dosing regimen and 20.5-65.0 mg/L in 16 patients receiving an initial two-week dose of 300 mg. The newly developed UPLC-MS/MS method met all criteria for accuracy, precision and stability, confirming its suitability for clinical use in monitoring ocrelizumab levels in multiple sclerosis patients.

• Klíčová slova
• Antibodies, Liquid chromatography, Mass spectrometry, Multiple sclerosis, Ocrelizumab, Serum,
• MeSH
• chromatografie kapalinová metody   MeSH
• humanizované monoklonální protilátky * terapeutické užití   krev   MeSH
• lidé MeSH
• monitorování léčiv metody   MeSH
• roztroušená skleróza * farmakoterapie   krev   MeSH
• tandemová hmotnostní spektrometrie * metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• humanizované monoklonální protilátky * MeSH
• ocrelizumab MeSH Prohlížeč

BACKGROUND: Pazopanib, an anti-angiogenic multitarget tyrosine kinase inhibitor, has been approved for the treatment of metastatic renal cell carcinoma and soft tissue sarcoma. However, its recommended dose does not always produce consistent outcomes, with some patients experiencing adverse effects or toxicity. This variability is due to differences in the systemic exposure to pazopanib. This review aimed to establish whether sufficient evidence exists for the routine or selective therapeutic drug monitoring of pazopanib in adult patients with approved indications. METHODS: A systematic search of the PubMed and Web of Science databases using search terms related to pazopanib and therapeutic drug monitoring yielded 186 and 275 articles, respectively. Ten articles associated with treatment outcomes or toxicity due to drug exposure were selected for review. RESULTS: The included studies were evaluated to determine the significance of the relationship between drug exposure/Ctrough and treatment outcomes and between drug exposure and toxicity. A relationship between exposure and treatment outcomes was observed in 5 studies, whereas the trend was nonsignificant in 4 studies. A relationship between exposure and toxicity was observed in 6 studies, whereas 2 studies did not find a significant relationship; significance was not reported in 3 studies. CONCLUSIONS: Sufficient evidence supports the therapeutic drug monitoring of pazopanib in adult patients to improve its efficacy and/or safety in the approved indications.

• MeSH
• indazoly * terapeutické užití   MeSH
• inhibitory angiogeneze * terapeutické užití   farmakokinetika   MeSH
• karcinom z renálních buněk * farmakoterapie   MeSH
• lidé MeSH
• monitorování léčiv * metody   MeSH
• nádory ledvin * farmakoterapie   MeSH
• pyrimidiny * terapeutické užití   farmakokinetika   MeSH
• sarkom * farmakoterapie   MeSH
• sulfonamidy * terapeutické užití   farmakokinetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH
• Názvy látek
• indazoly * MeSH
• inhibitory angiogeneze * MeSH
• pazopanib MeSH Prohlížeč
• pyrimidiny * MeSH
• sulfonamidy * MeSH

Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.

• Klíčová slova
• Aripiprazole, Olanzapine, Personalised medicine, Pharmacokinetics, Quetiapine, Risperidone,
• MeSH
• antipsychotika * farmakokinetika   terapeutické užití   MeSH
• lidé MeSH
• monitorování léčiv * metody   MeSH
• schizofrenie farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

OBJECTIVES: The objective of this study was to develop a population pharmacokinetic model of meropenem in a heterogeneous population of patients with a serious bacterial infection in order to propose dosing optimisation leading to improved achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target. METHODS: A total of 174 meropenem serum levels obtained from 144 patients during therapeutic drug monitoring were analysed using a non-linear mixed-effects modelling approach and Monte Carlo simulation was then used to compare various dosing regimens in order to optimise PK/PD target attainment. RESULTS: The meropenem volume of distribution of the patient population was 54.95 L, while clearance started at 3.27 L/hour and increased by 0.91 L/hour with each 1 mL/s/1.73 m2 of estimated glomerular filtration rate. Meropenem clearance was also 0.31 L/hour higher in postoperative patients with central nervous system infection. Meropenem administration by continuous infusion showed a significantly higher probability of attaining the PK/PD target than a standard 30 min infusion (95.3% vs 49.5%). CONCLUSIONS: A daily meropenem dose of 3 g, 6 g and 10.5 g administered by continuous infusion was shown to be accurate for patients with moderate to severe renal impairment, normal renal function to mild renal impairment and augmented renal clearance, respectively.

• Klíčová slova
• administration, intravenous, critical care, drug monitoring, pharmacy service, hospital, practice guideline,
• MeSH
• antibakteriální látky * farmakokinetika   aplikace a dávkování   MeSH
• bakteriální infekce * farmakoterapie   MeSH
• biologické modely * MeSH
• dospělí MeSH
• intravenózní infuze MeSH
• lidé středního věku MeSH
• lidé MeSH
• meropenem * farmakokinetika   aplikace a dávkování   MeSH
• metoda Monte Carlo MeSH
• monitorování léčiv metody   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antibakteriální látky * MeSH
• meropenem * MeSH