Therapeutic Drug Monitoring最新文献

{"title":"A Validated Assay to Quantify Osimertinib and Its Metabolites, AZ5104 and AZ7550, from Microsampled Dried Blood Spots and Plasma.","authors":"Bharat Venkatesh, Alex Yuile, Matthew J McKay, Sathya Narayanan, Helen Wheeler, Malinda Itchins, Nick Pavlakis, Stephen J Clarke, Mark P Molloy","doi":"10.1097/FTD.0000000000001157","DOIUrl":"10.1097/FTD.0000000000001157","url":null,"abstract":"<p><strong>Background: </strong>Osimertinib is an oral small-molecule tyrosine kinase receptor inhibitor used to treat non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor mutation. Patients may experience drug toxicity and require dose deescalation. The study aimed to quantitate osimertinib and its 2 active metabolites, AZ5104 and AZ7550, in microsampled dried blood spots (DBS) collected from patients with NSCLC using a hemaPEN device and compare them with plasma drug levels.</p><p><strong>Methods: </strong>A 6-min ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed and validated using plasma and DBS. The accuracy, selectivity, matrix effect, recovery, and stability were assessed using bioanalytical validation criteria. The hematocrit effect was investigated in DBS. Drug levels were measured in 15 patients with NSCLC, and the Bland-Altman method was used to compare measurements between plasma and DBS.</p><p><strong>Results: </strong>The validated assay determined accurate and precise quantities, respectively, for osimertinib in both plasma (93.2%-99.3%; 0.2%-2.3%) and DBS (96.7%-99.6%; 0.5%-10.3%) over a concentration of 1-729 ng/mL. The osimertinib metabolites, AZ5104 and AZ7550, were similarly validated in accordance with bioanalytical guidelines. For 30%-60% patient hematocrit, no hematocrit bias was observed with DBS for all analytes. The Bland-Altman method showed high concordance between plasma and DBS analyte levels. Stability experiments revealed that osimertinib and its metabolites were poorly stable in plasma at room temperature, whereas all analytes were stable in DBS for 10 days at room temperature.</p><p><strong>Conclusions: </strong>The measurement of osimertinib, AZ5104, and AZ7550 from hemaPEN microsampled DBS is a convenient and reliable approach for therapeutic drug monitoring that produces measurements consistent with plasma drug levels.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"332-343"},"PeriodicalIF":2.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11078286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139543080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Drug Monitoring of Pazopanib in Renal Cell Carcinoma and Soft Tissue Sarcoma: A Systematic Review.","authors":"Miroslav Turjap, Marta Pelcová, Jana Gregorová, Pavel Šmak, Hiroko Martin, Jan Štingl, Ondřej Peš, Jan Juřica","doi":"10.1097/FTD.0000000000001206","DOIUrl":"10.1097/FTD.0000000000001206","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Sufficient evidence supports the therapeutic drug monitoring of pazopanib in adult patients to improve its efficacy and/or safety in the approved indications.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":"46 3","pages":"321-331"},"PeriodicalIF":2.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Guidance for Dosing and Monitoring Oral Antihormonal Drugs in Patients with Breast Cancer After Roux-en-Y Gastric Bypass.","authors":"Jurjen S Kingma, Niels W L Peeters, Catherijne A J Knibbe, Mariette J Agterof, Wouter J M Derksen, Desirée M T Burgers, Marcel P H van den Broek","doi":"10.1097/FTD.0000000000001159","DOIUrl":"10.1097/FTD.0000000000001159","url":null,"abstract":"<p><strong>Abstract: </strong>Obesity is associated with an increased risk of cancers, such as breast cancer. Roux-en-Y gastric bypass (RYGB) is a common surgical intervention used to induce weight loss, reduce comorbidities, and improve overall survival. Due to alterations in the gastrointestinal tract, RYGB is associated with changes in oral drug disposition, which can affect treatment outcomes. Oral antihormonal agents were monitored in 9 patients who previously underwent RYGB. The results of therapeutic drug monitoring and estradiol concentrations were analyzed, and a review of the relevant literature was performed. As only 1 of the 6 patients prescribed tamoxifen achieved a therapeutic endoxifen concentration with the standard dose of 20 mg/d, a higher starting dose of 40 mg/d was recommended to increase the probability of attaining a therapeutic plasma concentration. All patients with decreased CYP2D6 metabolic activity could not achieve therapeutic plasma concentrations; therefore, CYP2D6 genotyping was recommended before the initiation of tamoxifen therapy to identify patients who should be switched to aromatase inhibitors. Anastrozole and letrozole exposure in patients who underwent RYGB patients appeared sufficient, with no dose adjustment required. However, until more data become available, monitoring aromatase inhibitor efficacy is recommended. Monitoring the drug concentrations is a viable option; however, only indicative data on therapeutic drug monitoring are available. Therefore, estradiol concentrations should be measured.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"404-409"},"PeriodicalIF":2.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138452643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive Performance of a Gentamicin Pharmacokinetic Model in Term Neonates with Perinatal Asphyxia Undergoing Controlled Therapeutic Hypothermia.","authors":"Marlotte A A van der Veer, Timo R de Haan, Linda G W Franken, Floris Groenendaal, Peter H Dijk, Willem P de Boode, Sinno Simons, Koen P Dijkman, Henrica L M van Straaten, Monique Rijken, Filip Cools, Debbie H G M Nuytemans, Anton H van Kaam, Yuma A Bijleveld, Ron A A Mathôt","doi":"10.1097/FTD.0000000000001166","DOIUrl":"10.1097/FTD.0000000000001166","url":null,"abstract":"<p><strong>Background: </strong>Model validation procedures are crucial when population pharmacokinetic (PK) models are used to develop dosing algorithms and to perform model-informed precision dosing. We have previously published a population PK model describing the PK of gentamicin in term neonates with perinatal asphyxia during controlled therapeutic hypothermia (TH), which showed altered gentamicin clearance during the hypothermic phase dependent on gestational age and weight. In this study, the predictive performance and generalizability of this model were assessed using an independent data set of neonates with perinatal asphyxia undergoing controlled TH.</p><p><strong>Methods: </strong>The external data set contained a subset of neonates included in the prospective observational multicenter PharmaCool Study. Predictive performance was assessed by visually inspecting observed-versus-predicted concentration plots and calculating bias and precision. In addition, simulation-based diagnostics, model refitting, and bootstrap analyses were performed.</p><p><strong>Results: </strong>The external data set included 323 gentamicin concentrations of 39 neonates. Both the model-building and external data set included neonates from multiple centers. The original gentamicin PK model predicted the observed gentamicin concentrations with adequate accuracy and precision during all phases of controlled TH. Model appropriateness was confirmed with prediction-corrected visual predictive checks and normalized prediction distribution error analyses. Model refitting to the merged data set (n = 86 neonates with 935 samples) showed accurate estimation of PK parameters.</p><p><strong>Conclusions: </strong>The results of this external validation study justify the generalizability of the gentamicin dosing recommendations made in the original study for neonates with perinatal asphyxia undergoing controlled TH (5 mg/kg every 36 or 24 h with gestational age 36-41 and 42 wk, respectively) and its applicability in model-informed precision dosing.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"376-383"},"PeriodicalIF":2.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11078285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139576404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the Rare Presentation of Acetylsalicylate Overdose: Grand Round.","authors":"Saeko Kohara, Yoshito Kamijo, Ryoko Kyan, Tsuyoshi Hishikawa, Ichiro Okada, Eiju Hasegawa","doi":"10.1097/FTD.0000000000001187","DOIUrl":"10.1097/FTD.0000000000001187","url":null,"abstract":"<p><strong>Background: </strong>This case report highlights a rare occurrence of aspirin overdose presenting only as severe coagulopathy.</p><p><strong>Case presentation: </strong>An 85-year-old woman was admitted to the hospital with multiple lumbar vertebral compression fractures causing severe back pain. The patient had self-medicated with excessive consumption of Bufferin A containing 330 mg of aspirin. On arrival, she showed no typical symptoms of salicylate toxicity, such as nausea, vomiting, hyperventilation, tinnitus, or hearing loss. However, blood work revealed a significant decrease in vitamin K-dependent coagulation factors leading to coagulopathy. The administration of 20-mg menatetrenone (vitamin K) resulted in rapid improvement in coagulation abnormalities. The patient's blood salicylate level was later determined to be 42.7 mg/dL.</p><p><strong>Discussion: </strong>Acute salicylate poisoning is known to cause coagulopathy because of the inhibition of vitamin K-dependent coagulation factors. However, this case is unique because it demonstrates coagulopathy as the sole manifestation of aspirin toxicity without any other symptoms.</p><p><strong>Conclusions: </strong>This case highlights the importance of considering the possibility of aspirin toxicity in patients with coagulopathy, especially those who are regularly consuming aspirin.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"288-290"},"PeriodicalIF":2.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139698390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tocilizumab Dose Tapering Based on a Model-Based Algorithm is Feasible in Clinical Practice: A Short Communication.","authors":"Femke Hooijberg, Zohra Layegh, Maureen Leeuw, Laura Boekel, Stefan P H van den Berg, Jill Ruwaard, Carla Bastida, Alwin D R Huitema, Sara Pel, Ori Elkayam, Annick de Vries, Mike Nurmohamed, Theo Rispens, Thomas P C Dorlo, Gertjan Wolbink","doi":"10.1097/FTD.0000000000001168","DOIUrl":"10.1097/FTD.0000000000001168","url":null,"abstract":"<p><strong>Background: </strong>Tocilizumab in the treatment of rheumatoid arthritis (RA) is a potential candidate for concentration-guided tapering because the standard dose of tocilizumab results in a wide range of serum concentrations, usually above the presumed therapeutic window, and an exposure-response relationship has been described. However, no clinical trials have been published to date on this subject. Therefore, the objective of this study was to assess the feasibility of the tapering of intravenous (iv) tocilizumab with the use of a pharmacokinetic model-based algorithm in RA patients.</p><p><strong>Methods: </strong>A randomized controlled trial with a double-blind design and follow-up of 24 weeks was conducted. RA patients who received the standard of tocilizumab for at least the past 24 weeks, which is 8 mg/kg every 4 weeks, were included. Patients with a tocilizumab serum concentration above 5 mg/L at trough were randomized between concentration-guided dose tapering, referred to as therapeutic drug monitoring (TDM), or the standard 8 mg/kg dose. In the TDM group, the tocilizumab dose was tapered with a recently published model-based algorithm to achieve a target concentration of 4-6 mg/L after 20 weeks of dose tapering.</p><p><strong>Results: </strong>Twelve RA patients were included and 10 were randomized between the TDM and standard dose group. The study was feasible regarding the predefined feasibility criteria and patients had a positive attitude toward therapeutic drug monitoring. In the TDM group, the tocilizumab trough concentration within patients decreased on average by 24.5 ± 18.3 mg/L compared with a decrease of 2.8 ± 12 mg/L in the standard dose group. None of the patients in the TDM group reached the drug range of 4-6 mg/L. Instead, tocilizumab concentrations of 1.6 and 1.5 mg/L were found for the 2 patients who completed follow-up on the tapered dose. No differences in RA disease activity were observed between the 2 study groups.</p><p><strong>Conclusions: </strong>This study was the first to show that it is feasible to apply a dose-reduction algorithm based on a pharmacokinetic model in clinical practice. However, the current algorithm needs to be optimized before it can be applied on a larger scale.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"410-414"},"PeriodicalIF":2.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139576442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Systematic Critical Review of Clinical Pharmacokinetics of Torasemide.","authors":"Abdul Wasay Sherazi, Ammara Zamir, Anees Ur Rehman, Waseem Ashraf, Imran Imran, Hamid Saeed, Abdul Majeed, Zikria Saleem, Majid Aziz, Faleh Alqahtani, Muhammad Fawad Rasool","doi":"10.1097/FTD.0000000000001141","DOIUrl":"10.1097/FTD.0000000000001141","url":null,"abstract":"<p><strong>Purpose: </strong>Torasemide is a potassium-sparing loop diuretic used to treat fluid retention associated with congestive heart failure and kidney and hepatic diseases. This systematic review was conducted to combine all accessible data on the pharmacokinetics (PK) of torasemide in healthy and diseased populations, which may help clinicians avert adverse drug reactions and determine the correct dosage regimen.</p><p><strong>Methods: </strong>Four databases were systematically searched to screen for studies associated with the PK of torasemide, and 21 studies met the eligibility criteria. The review protocol was registered in the PROSPERO database (CRD42023390178).</p><p><strong>Results: </strong>A decrease in maximum plasma concentration (C max ) was observed for torasemide after administration of the prolonged-release formulation in comparison to that after administration of the immediate-release formulation, that is, 1.12 ± 0.17 versus 1.6 ± 0.2 mcg/mL. After administering an oral dose of torasemide, a 2-fold increase in the area under the concentration-time curve (AUC) was reported in patients with congestive heart failure compared with the healthy population. Moreover, the patients with renal failure (clearance < 30 mL/min) showed an increase in value of AUC 0-∞ that is, 42.9 versus 8.091 mcg.h -1 .mL -1 compared with healthy subjects. In addition, some studies have reported interactions with different drugs, in which irbesartan showed a slight increase in the AUC 0-∞ of torasemide, whereas losartan and empagliflozin did not.</p><p><strong>Conclusions: </strong>The current review summarizes all available PK parameters of torasemide that may be beneficial for avoiding drug-drug interactions in subjects with renal and hepatic dysfunction and for predicting doses in patients with different diseases.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"309-320"},"PeriodicalIF":2.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Bedaquiline and Delamanid Pharmacokinetics on Sputum Culture Conversion and Adverse Events in Drug-Resistant Tuberculosis.","authors":"Anuj K Bhatnagar, Agibothu Kupparam Hemanthkumar, Mariappan Muthu Vijayalakshmi, Vikram Vohra, Chandrasekaran Padmapriyadarsini, Paranchi Murugesan Ramesh, Gaurav Taneja, Vijay Nathu Chavan, Bharathi Jeyadeepa, Namrata Kaur Bhui, Rajesh Solanki","doi":"10.1097/FTD.0000000000001164","DOIUrl":"10.1097/FTD.0000000000001164","url":null,"abstract":"<p><strong>Background: </strong>Pharmacokinetic studies of bedaquiline and delamanid in patients with pre-extensively drug-resistant tuberculosis (pre-XDR TB) will help in the optimization of these drugs for both culture conversion and adverse events.</p><p><strong>Methods: </strong>A prospective cohort of 165 adult patients (56% male with mean [SD] age 29 [9.7] years) with pre-XDR TB was treated with bedaquiline, delamanid, clofazimine, and linezolid for 24 weeks at 5 sites in India. Bedaquiline was administered at 400 mg daily for 2 weeks followed by 200 mg thrice weekly for 22 weeks, whereas delamanid was administered at 100 mg twice daily. In 23 consenting participants at 8 and 16 weeks of treatment, blood was collected at 0, 2, 4, 5, 6, 8, 12, and 24 hours postdosing for an intense pharmacokinetic study. Pharmacokinetic parameters were correlated with sputum culture conversion and adverse events.</p><p><strong>Results: </strong>The mean (SD) age and weight of patients were 30 (10) years and 54 kg, respectively. The median minimum concentration (C min ) and time-concentration curve (AUC) for bedaquiline, respectively, were 0.6 mcg/mL and 27 mcg/mL·h at week 8 and 0.8 mcg/mL and 36 mcg/mL·h at week 16, suggesting drug accumulation over time. The median C min and AUC of delamanid, respectively, were 0.17 mcg/mL and 5.1 mcg/mL·h at week 8 and 0.20 mcg/mL and 7.5 mcg/mL·h at week 16. Delay in sputum conversion was observed in patients with drug concentrations lower than the targeted concentration. At weeks 8 and 16, 13 adverse events were observed. Adverse events were resolved through symptomatic treatment. Body mass index was found to be significantly associated with drug-exposure parameters.</p><p><strong>Conclusions: </strong>Bedaquiline and delamanid when co-administered exhibit plasma drug levels within the targeted concentrations, showing an exposure-response relationship.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"363-369"},"PeriodicalIF":2.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11078291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139075109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fast and Sensitive Analysis of Fosfomycin in Human Plasma Microsamples Using Liquid Chromatography-Tandem Mass Spectrometry for Therapeutic Drug Monitoring.","authors":"Rossella Barone, Matteo Conti, Beatrice Giorgi, Milo Gatti, Pier Giorgio Cojutti, Pierluigi Viale, Federico Pea","doi":"10.1097/FTD.0000000000001158","DOIUrl":"10.1097/FTD.0000000000001158","url":null,"abstract":"<p><strong>Background: </strong>Fosfomycin is an antibiotic recently repurposed as a potential combination treatment for difficult-to-treat Gram-negative bacterial infections. The pharmacokinetic features of fosfomycin have demonstrated that different pathophysiologic alterations may affect its exposure. Therapeutic drug monitoring may improve real-time management of fosfomycin therapy in different clinical scenarios.</p><p><strong>Objectives: </strong>To develop and validate a fast and sensitive liquid chromatography - tandem mass spectrometry method for measuring fosfomycin in human plasma microsamples (3 µL).</p><p><strong>Methods: </strong>Analysis was preceded by a user-friendly pre-analytical single-step process performed via a rapid chromatographic run of 2.5 minutes, followed by negative electrospray ionization and detection on a high-sensitivity triple quadrupole tandem mass spectrometer operated in the multiple reaction monitoring mode. European Medicines Agency guidelines were used to validate the specificity, sensitivity, linearity, precision, accuracy, matrix effects, extraction recovery, limits of quantification, and stability of the analytical method.</p><p><strong>Results: </strong>The new assay produced accurate (BIAS%: 0.9-9.1) and precise (coefficient of variation [CV]%: 8.1-9.5) measurements of fosfomycin over a concentration range of 1-1000 mg/L. Overall, analyte recovery was consistent (mean values: 91.2%-97.2%) at all tested concentration levels. The analyte was also stable in human plasma and the final extract under various storage conditions. The clinical applicability of the assay was confirmed through quantitation of plasma samples obtained from patients.</p><p><strong>Conclusions: </strong>A sensitive liquid chromatography - tandem mass spectrometry method for measuring fosfomycin in plasma was developed and validated according to the European Medicines Agency criteria. Quantitation of fosfomycin in clinical plasma samples confirmed that the assay is suitable for therapeutic drug monitoring in clinical scenarios.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"384-390"},"PeriodicalIF":2.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138452647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic Variability of Rufinamide and Stiripentol in Children with Refractory Epilepsy: A Retrospective Study of Therapeutic Drug Monitoring from the National Epilepsy Centers in Denmark and Norway.","authors":"Katrine Heger, Margrete Larsen Burns, Marina Nikanorova, Svein I Johannessen, Cecilie Johannessen Landmark","doi":"10.1097/FTD.0000000000001219","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001219","url":null,"abstract":"<p><strong>Background: </strong>Rufinamide and stiripentol, orphan drugs used in Lennox-Gastaut and Dravet syndromes, respectively, are antiseizure medications (ASMs), often administered to children; however, pharmacokinetic studies are lacking. The authors compared the pharmacokinetic variability of these drugs with respect to the dose, serum concentrations, comedication, age, and duration of treatment.</p><p><strong>Methods: </strong>Children and adolescents (<18 years) whose serum concentrations were measured were retrospectively identified from the therapeutic drug monitoring (TDM) databases at 2 national epilepsy centers in Norway and Denmark (2012-2021).</p><p><strong>Results: </strong>Data from 165 patients (56% boys/44% girls) treated with rufinamide and 52 patients (50% boys/50% girls) treated with stiripentol were included. For rufinamide, the median age was 10 (range 2-17) years, dose 23 (3-73) mg/d, and serum concentration 34 (3-227) µmol/L [8.1 mg/L (0.71-54.0 mg/L)]. For stiripentol, the median age was 8.5 (range 1-17) years, dose 37 (18-76) mg/d, and serum concentration 33 (4-113) µmol/L [7.7 mg/L (0.93-26.3 mg/L)]. The concomitant use of 1-9 other ASMs during the data collection was noted. Pharmacokinetic variability, calculated as the concentration/(dose/kg) ratio, ranged from 0.26 to 11.31 (µmol/L)/(mg/kg) for rufinamide and 0.17-1.52 (µmol/L)/(mg/kg) for stiripentol. The intraindividual coefficients of variation ranged widely, from 5% to 110% for rufinamide and 11%-117% for stiripentol. The treatment period was at least 5 years in 50% of patients. No statistically significant effects of age, sex, or ASM comedication were observed, possibly due to the small sample size and heterogeneous groups with variable seizure situations, comorbidities, and changes in comedication and physiology.</p><p><strong>Conclusions: </strong>This study demonstrates considerable pharmacokinetic variability in and between patients for both drugs and similar use in terms of age, burden of comedication and retention rates. TDM may be useful in the clinical setting to monitor and optimize treatment in this vulnerable patient group.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140959602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}