RESUMEN

BACKGROUND: Paclitaxel is a promising anticancer drug for patients with ovarian, breast, lung, gastrointestinal, genitourinary, prostate, and head-and-neck cancers. Paclitaxel follows nonlinear pharmacokinetics. The major metabolite of paclitaxel is 6-alpha-hydroxy paclitaxel, mediated by CYP2C8, while metabolism to two of its minor metabolites, 3'-p-hydroxypaclitaxel and 6a, 3'- p-dihydroxypaclitaxel, is catalyzed by CYP3A4. Therapeutic drug monitoring of paclitaxel could be a promising approach to improve the efficacy and safety of paclitaxel correct personalized doses and improve the overall benefit-risk ratio. A novel and highly sensitive chromatographic method for the detection of paclitaxel and its metabolite has been proposed that allows quantification in human plasma with 100% accuracy in terms of recovery without significant intraday or interday variations. MATERIALS AND METHODS: The present study was planned following bioanalytical method validation guidance according to the U.S. Food and Drug Administration requirements. The validation of the analytical procedure was performed as per ICH Q2(R1) guidelines. It was done to assure the reliability of the results obtained for various parameters such as linearity, accuracy, precision, limit of detection (LOD), limit of quantification, robustness, stability, and system suitability. RESULTS: The specificity of the method was established by ensuring no interference with peak obtained from paclitaxel and 6-alpha-hydroxy paclitaxel. LOD was found to be 0.05 and 0.033 while the limit of quantitation was 0.14 and 0.099 for paclitaxel and 6-alpha-hydroxy paclitaxel, respectively. Median (±interquartile range) accuracy for paclitaxel and 6-alpha-hydroxy paclitaxel was found to be 102.73 (±13.581) and 100.87 (±7.573), respectively. CONCLUSION: This novel method of simultaneous detection of paclitaxel and its major metabolite 6-alpha-hydroxy paclitaxel demonstrated significant resolution and was sensitive enough for its quantification in human plasma.

Asunto(s)

Antineoplásicos Fitogénicos , Límite de Detección , Paclitaxel , Paclitaxel/sangre , Paclitaxel/farmacocinética , Paclitaxel/análogos & derivados , Humanos , Cromatografía Líquida de Alta Presión/métodos , Reproducibilidad de los Resultados , Antineoplásicos Fitogénicos/sangre , Antineoplásicos Fitogénicos/farmacocinética , Monitoreo de Drogas/métodos

RESUMEN

Despite a higher safety profile compared to vitamin K antagonists, rivaroxaban therapy is still connected with multiple adverse effects, such as a high risk of bleeding. Thus, therapeutic drug monitoring (TDM) of rivaroxaban concentrations is suggested. An alternative to plasma samples can be dried blood spots (DBS), which minimize the cost of sample storage and transport. In this study, we developed a UPLC-MS/MS method for the analysis of rivaroxaban in DBS and plasma samples. Chromatographic separation was achieved on a Zorbax Eclipse Plus C18 column (2.1 × 100 mm; 3.5 µm, Agilent Technologies Inc., Santa Clara, CA, USA) with a mobile phase consisting of water and acetonitrile, both containing 0.1% formic acid. The analytes were detected using a positive ionization mode by multiple reaction monitoring. We validated the method according to ICH guidelines. The precision and accuracy were satisfactory. Extraction recovery was approximately 57% and 66% for DBS and plasma samples, respectively. A high correlation between rivaroxaban concentrations in plasma and DBS samples collected from patients was confirmed with Deming regression. The suitability of both sampling techniques for the rivaroxaban TDM was also verified by Bland-Altman plots based on DBS-predicted and observed plasma concentrations. In addition, we found a significant relationship between rivaroxaban concentrations and coagulation parameters, including prothrombin time (PT) and international normalized ratio (INR).

Asunto(s)

Pruebas con Sangre Seca , Monitoreo de Drogas , Rivaroxabán , Espectrometría de Masas en Tándem , Trombosis de la Vena , Rivaroxabán/sangre , Humanos , Espectrometría de Masas en Tándem/métodos , Pruebas con Sangre Seca/métodos , Cromatografía Líquida de Alta Presión/métodos , Trombosis de la Vena/sangre , Trombosis de la Vena/tratamiento farmacológico , Monitoreo de Drogas/métodos , Inhibidores del Factor Xa/sangre , Reproducibilidad de los Resultados , Cromatografía Líquida con Espectrometría de Masas

RESUMEN

BACKGROUND: The goal of this study was to develop and validate a UPLC-MS/MS method for simultaneous mea-surement of 13 AEDs, including carbamazepine, oxcarbazepine, lamotrigine, levetiracetam, topiramate, primidone, zonisamide, gabapentin, lacosamide, perampanel, pregabalin, rufinamide, and vigabatrin, in whole blood samples. METHODS: A UPLC-MS/MS method for simultaneous determination of 13 AEDs in whole blood was developed, and validation was conducted for accuracy, precision, limit of quantification (LOQ), matrix effect, and stability. Our method was compared to two different hospitals using UPLC-MS/MS. RESULTS: All AEDs exhibited linearity across the AMR (analytical measurement range), with R2 values ranging from 0.994 to 1.000. The imprecision and inaccuracy for low and high quality control (QC) levels were within an acceptable range, with the coefficient of variation (CV) < 15%. The LOQ was 0.62 µg/mL for carbamazepine, 1.61 µg/mL for oxcarbazepine, 1.30 µg/mL for lamotrigine, 13.20 µg/mL for levetiracetam, 1.26 µg/mL for topira-mate, 1.01 µg/mL for primidone, 1.59 µg/mL for zonisamide, 1.09 µg/mL for lacosamide, 1.61 µg/mL for gabapentin, 0.50 µg/mL for pregabalin, 0.07 ng/mL for perampanel, 3.00 µg/mL for rufinamide, and 2.06 µg/mL for vigabatrin. All AEDs demonstrated acceptable assay parameters for carryover, stability, and matrix effects. Moreover, the assay showed satisfactory results compared to two different hospitals with a bias of less than 15%. CONCLUSIONS: We successfully developed and validated a fast and robust UPLC-MS/MS method for routine therapeutic drug monitoring of thirteen antiepileptic drugs simultaneously.

Asunto(s)

Anticonvulsivantes , Límite de Detección , Espectrometría de Masas en Tándem , Anticonvulsivantes/sangre , Anticonvulsivantes/análisis , Espectrometría de Masas en Tándem/métodos , Espectrometría de Masas en Tándem/normas , Humanos , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Líquida de Alta Presión/normas , Reproducibilidad de los Resultados , Monitoreo de Drogas/métodos , Monitoreo de Drogas/normas , Estándares de Referencia , Cromatografía Líquida con Espectrometría de Masas

RESUMEN

BACKGROUND: The first purpose of this study was to determine whether a measurement of the level of direct oral anticoagulants (DOACs) was possible with heparin-calibrated chromogenic anti-factor Xa activity (AXA). The second purpose of this study was to evaluate whether the antidote treatment decision level (30 or 50 ng/mL of DOAC) can be determined by unfractionated heparin (UHF)/low molecular weight heparin (LMWH)-calibrated AXA. METHODS: AXA was measured by using two reagents and dedicated analyzers (Sysmex CS-5100 analyzer and STA R Max3). Four types of calibrators were used: 1) Stago DOAC (rivaroxaban, edoxaban, and apixaban)-specific calibrator, 2) Stago LMWH calibrator, 3) Sysmex UHF calibrator, and 4) Sysmex LMWH calibrator. Regression analysis was used between assays. Receiver operating characteristic (ROC) curves were performed, and the concordance rate was calculated. RESULTS: The correlation coefficients were in the range of 0.75 - 0.91 for rivaroxaban and 0.81 - 0.94 for apixaban. The correlation coefficient between edoxaban-calibrated AXA and Sysmex LMWH/Sysmex UHF calibrator-calibrated AXA was low (r = 0.47). Overall correlation between DOAC-calibrated AXA and Stago LMWH-calibrated AXA was linear, at only low concentration in all three DOACs. The concordance rate (89.3 - 100%) is good for de-termining the antidote management level by UFH/LMWH-calibrated AXA, compared with those of DOAC-calibrated AXA in rivaroxaban and apixaban. The concordance rate ranged from 63% to 67% between Sysmex UFH/ LMWH-calibrated AXA and edoxaban-calibrated AXA. CONCLUSIONS: The findings of our study suggest limitations in calculating accurate concentrations, when using UFH/LMWH-calibrated AXA to measure DOAC. This study demonstrates that UFH/LMWH-calibrated AXA may be useful in determining the presence of DOACs at the cutoff level for the antidote treatment in rivarovaban and apixaban. However, in edoxaban, UFH/LMWH-calibrated AXA could not accurately measure the presence of DOACs at the cutoff for antidote treatment.

Asunto(s)

Inhibidores del Factor Xa , Heparina , Pirazoles , Piridinas , Piridonas , Rivaroxabán , Tiazoles , Piridonas/análisis , Humanos , Pirazoles/análisis , Rivaroxabán/sangre , Rivaroxabán/análisis , Inhibidores del Factor Xa/farmacología , Calibración , Heparina/análisis , Anticoagulantes/farmacología , Anticoagulantes/análisis , Curva ROC , Reproducibilidad de los Resultados , Pruebas de Coagulación Sanguínea/métodos , Pruebas de Coagulación Sanguínea/instrumentación , Pruebas de Coagulación Sanguínea/normas , Monitoreo de Drogas/métodos , Monitoreo de Drogas/instrumentación

RESUMEN

INTRODUCTION: High-dose methotrexate (HDMTX) use can be limited by the development of acute kidney injury (AKI). Early AKI detection is paramount to prevent further renal injury and irreversible toxicities. This study sought to determine whether early elimination patterns of MTX would be useful as a biomarker of AKI in HDMTX treatment. METHODS: This retrospective cohort study included two sites that collected ≥2 MTX levels within 16 h from completion of MTX infusion. Early levels were tagged and MTX elimination half-life (t½) were calculated from combinations of two of three different early time periods. Receiver operating characteristic (ROC) curves were synthesized for each elimination t½ (biomarker) with respect to AKI and delayed methotrexate elimination (DME); the biomarker with the highest area under the ROC curve (AUC) was tested in a multiple variable logistic regression model. RESULTS: Data from 169 patients who received a total of 556 courses of HDMTX were analyzed. ROC analysis revealed MTX elimination t½ calculated from the second and third time periods had the highest AUC for AKI at 0.62 (interquartile range [IQR] 0.56-0.69) and DME at 0.86 (IQR 0.73-1.00). After adjusting for age, sex, dose (mg/m2), infusion duration, HDMTX course, and baseline estimated glomerular filtration rate, it remained significant for AKI with an OR of 1.29 and 95% confidence interval of 1.03-1.65. CONCLUSION: Early MTX elimination t½ measured within 16 h of infusion completion was significantly associated with the development of AKI and serves as an early clearance biomarker that may identify patients who benefit from increased hydration, augmented leucovorin rescue, and glucarpidase administration.

Asunto(s)

Lesión Renal Aguda , Monitoreo de Drogas , Metotrexato , Humanos , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/inducido químicamente , Metotrexato/farmacocinética , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Monitoreo de Drogas/métodos , Anciano , Curva ROC , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Biomarcadores , Adulto

RESUMEN

Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic (PK/PD) parameters is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised paediatric host. In neonates and children, infections account for a high percentage of hospital admissions, and anti-infectives are the most used drugs. However, paediatric PK/PD studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals-usually used off-label in paediatrics-to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the PK parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, paediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring. The aim of this document, developed jointly by the Spanish Society of Hospital Pharmacy and the Spanish Society of Paediatric Infectious Diseases, is to describe the available evidence on the indications for therapeutic drug monitoring (TDM) of antibiotics and antifungals in newborn and paediatric patients, and to provide practical recommendations for TDM in routine clinical practice to optimise their dosing, efficacy and safety. Of antibiotics and antifungals in the paediatric population.

Asunto(s)

Antibacterianos , Antifúngicos , Monitoreo de Drogas , Humanos , Recién Nacido , Monitoreo de Drogas/métodos , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Niño , Antifúngicos/farmacocinética , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Lactante , Preescolar

RESUMEN

PURPOSE OF REVIEW: To highlight the recent evidence for antibiotic pharmacokinetics and pharmacodynamics (PK/PD) in enhancing patient outcomes in sepsis and septic shock. We also summarise the limitations of available data and describe future directions for research to support translation of antibiotic dose optimisation to the clinical setting. RECENT FINDINGS: Sepsis and septic shock are associated with poor outcomes and require antibiotic dose optimisation, mostly due to significantly altered pharmacokinetics. Many studies, including some randomised controlled trials have been conducted to measure the clinical outcome effects of antibiotic dose optimisation interventions including use of therapeutic drug monitoring. Current data support antibiotic dose optimisation for the critically ill. Further investigation is required to evolve more timely and robust precision antibiotic dose optimisation approaches, and to clearly quantify whether any clinical and health-economic benefits support expanded use of this treatment intervention. SUMMARY: Antibiotic dose optimisation appears to improve outcomes in critically ill patients with sepsis and septic shock, however further research is required to quantify the level of benefit and develop a stronger knowledge of the role of new technologies to facilitate optimised dosing.

Asunto(s)

Antibacterianos , Enfermedad Crítica , Sepsis , Choque Séptico , Humanos , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Sepsis/tratamiento farmacológico , Choque Séptico/tratamiento farmacológico , Monitoreo de Drogas/métodos , Relación Dosis-Respuesta a Droga , Ensayos Clínicos Controlados Aleatorios como Asunto , Cuidados Críticos/métodos

RESUMEN

Due to interindividual variability in drug metabolism and pharmacokinetics, traditional isoniazid fixed-dose regimens may lead to suboptimal or toxic isoniazid concentrations in the plasma of patients with tuberculosis, contributing to adverse drug reactions, therapeutic failure, or the development of drug resistance. Achieving precision therapy for isoniazid requires a multifaceted approach that could integrate various clinical and genomic factors to tailor the isoniazid dose to individual patient characteristics. This includes leveraging molecular diagnostics to perform the comprehensive profiling of host pharmacogenomics to determine how it affects isoniazid metabolism, such as its metabolism by N-acetyltransferase 2 (NAT2), and studying drug-resistant mutations in the Mycobacterium tuberculosis genome for enabling targeted therapy selection. Several other molecular signatures identified from the host pharmacogenomics as well as other omics-based approaches such as gut microbiome, epigenomic, proteomic, metabolomic, and lipidomic approaches have provided mechanistic explanations for isoniazid pharmacokinetic variability and/or adverse drug reactions and thereby may facilitate precision therapy of isoniazid, though further validations in larger and diverse populations with tuberculosis are required for clinical applications. Therapeutic drug monitoring and population pharmacokinetic approaches allow for the adjustment of isoniazid dosages based on patient-specific pharmacokinetic profiles, optimizing drug exposure while minimizing toxicity and the risk of resistance. Current evidence has shown that with the integration of the host pharmacogenomics-particularly NAT2 and Mycobacterium tuberculosis genomics data along with isoniazid pharmacokinetic concentrations in the blood and patient factors such as anthropometric measurements, comorbidities, and type and timing of food administered-precision therapy approaches in isoniazid therapy can be tailored to the specific characteristics of both the host and the pathogen for improving tuberculosis treatment outcomes.

Asunto(s)

Antituberculosos , Isoniazida , Mycobacterium tuberculosis , Medicina de Precisión , Tuberculosis , Humanos , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Medicina de Precisión/métodos , Isoniazida/farmacocinética , Isoniazida/administración & dosificación , Isoniazida/efectos adversos , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Monitoreo de Drogas/métodos , Arilamina N-Acetiltransferasa/genética , Arilamina N-Acetiltransferasa/metabolismo , Farmacogenética , Farmacorresistencia Bacteriana/genética

RESUMEN

Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are antiviral medications primarily used to treat infections caused by cytomegalovirus (CMV), particularly in immunocompromised individuals such as solid organ transplant (SOT) recipients. Therapy with GCV is associated with significant side effects, including bone marrow suppression. Therefore, therapeutic drug monitoring (TDM) is mandatory for an appropriate balance between subtherapeutic and toxic drug levels. This study aimed to develop and validate three novel methods based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for GCV determination in serum (reference methodology), dried serum spots (DSS), and VAMS-Mitra™ devices. The methods were optimized and validated in the 0.1-25 mg/L calibration range. The obtained results fulfilled the EMA acceptance criteria for bioanalytical method validation. Assessment of DSS and VAMS techniques extended GCV stability to serum for up to a minimum of 49 days (at room temperature, with desiccant). Developed methods were effectively evaluated using 80 clinical serum samples from pediatric renal transplant recipients. Obtained samples were used for DSS, and dried serum VAMS samples were manually generated in the laboratory. The results of GCV determination using serum-, DSS- and VAMS-LC-MS/MS methods were compared using regression analysis and bias evaluation. The conducted statistical analysis confirmed the interchangeability between developed assays. The DSS and VAMS samples are more accessible and stable during storage, transport and shipment than classic serum samples.

Asunto(s)

Antivirales , Pruebas con Sangre Seca , Monitoreo de Drogas , Ganciclovir , Espectrometría de Masas en Tándem , Humanos , Monitoreo de Drogas/métodos , Pruebas con Sangre Seca/métodos , Espectrometría de Masas en Tándem/métodos , Ganciclovir/análogos & derivados , Ganciclovir/sangre , Ganciclovir/uso terapéutico , Antivirales/sangre , Antivirales/uso terapéutico , Cromatografía Liquida/métodos , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/tratamiento farmacológico , Valganciclovir/uso terapéutico , Valganciclovir/sangre , Niño

RESUMEN

This comprehensive review delves into the forefront of biosensor technologies and their critical roles in disease biomarker detection and therapeutic drug monitoring. It provides an in-depth analysis of various biosensor types and applications, including enzymatic sensors, immunosensors, and DNA sensors, elucidating their mechanisms and specific healthcare applications. The review highlights recent innovations such as integrating nanotechnology, developing wearable devices, and trends in miniaturisation, showcasing their transformative potential in healthcare. In addition, it addresses significant sensitivity, specificity, reproducibility, and data security challenges, proposing strategic solutions to overcome these obstacles. It is envisaged that it will inform strategic decision-making, drive technological innovation, and enhance global healthcare outcomes by synthesising multidisciplinary insights.

Asunto(s)

Técnicas Biosensibles , Monitoreo de Drogas , Técnicas Biosensibles/métodos , Humanos , Monitoreo de Drogas/métodos , Nanotecnología/métodos , Dispositivos Electrónicos Vestibles , Biomarcadores/análisis , Atención a la Salud

RESUMEN

The mTOR-inhibitor everolimus is a precision drug with antiepileptogenic properties approved for treatment of epilepsy in persons with tuberous sclerosis complex (TSC) in combination with other antiseizure medications (ASMs). However, the pharmacokinetic variability of everolimus is scarcely described, and the available information on pharmacokinetic interactions is scarce. The purpose of this study was to investigate pharmacokinetic variability of everolimus in patients with TSC, and the impact of age, sex and comedication. In this retrospective observational study we used anonymized data from medical records of patients with TSC using everolimus in Norway and Denmark, 2012 to 2020. Long-term therapeutic drug monitoring (TDM) identified inter-patient and intra-patient variability. The study included 59 patients, (36 females (61%)), median age 22 (range 3-59 years). Polytherapy was used in 50 patients (85%). The most frequently used ASMs were lamotrigine (n = 21), valproate (n = 17), and levetiracetam (n = 13). Blood concentrations of everolimus were measured in all patients. Pharmacokinetic variability of everolimus between patients was extensive, as demonstrated by a 24-fold variability from minimum-maximum concentration/dose (C/D)-ratios. The coefficient of variation (CV) for intra-patient (n = 59) and inter-patient variability (n = 47, ≥3 measurements) was 40% and 43%, respectively. The C/D-ratio of everolimus was 50% lower in 13 patients (22%) using enzyme-inducing ASMs compared to the 30 patients who did not (0.7 vs 1.4 ng/mL mg, P < .05). Age and sex were not significantly associated with changes in C/D-ratios of everolimus. Long-term TDM identified extensive variability in concentrations over time for everolimus both within and between patients, where comedication with enzyme-inducing ASMs was an important contributing factor. The findings suggest a need for TDM in patients with TSC treated with everolimus.

Asunto(s)

Anticonvulsivantes , Monitoreo de Drogas , Everolimus , Esclerosis Tuberosa , Humanos , Everolimus/farmacocinética , Everolimus/uso terapéutico , Everolimus/administración & dosificación , Everolimus/sangre , Esclerosis Tuberosa/tratamiento farmacológico , Esclerosis Tuberosa/complicaciones , Femenino , Masculino , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/administración & dosificación , Adulto , Estudios Retrospectivos , Monitoreo de Drogas/métodos , Persona de Mediana Edad , Adolescente , Noruega , Adulto Joven , Niño , Dinamarca , Preescolar , Epilepsia/tratamiento farmacológico , Quimioterapia Combinada , Interacciones Farmacológicas

RESUMEN

Polymyxin B (PB) and Polymyxin E (PE, also called colistin) are used as the last treatment resort for multidrug-resistant Gram-negative bacterial infections. The nephrotoxicity and neurotoxicity of polymyxins limit their clinical use, and guidelines recommend therapeutic drug monitoring (TDM) to optimize efficacy and reduce toxicity. However, there are limited analytical methods available for the determination of PB and PE. This study aimed to develop a simple and robust liquid chromatography with tandem mass spectrometry (LC-MS/MS) analytical method for determining the main compounds of PB and PE, namely PB1, PB2, ile-PB1, PE1, and PE2, in human plasma and to investigate of their pharmacokinetics in critically ill patients with the use of PB and PE, respectively. Plasma PB1, PB2, ile-PB1, PE1, and PE2 were chromatographically separated on a Welch LP-C18 column and detected using electrospray ionization mode coupled with multiple reaction monitoring. The calibration curve showed acceptable linearity over 20-10,000 ng/mL for PB1, PE1, and PE2 and 10-5000 ng/mL for PB2 and ile-PB1 in the plasma, respectively. After validation following approved guidelines, this method was successfully applied for PB and PE pharmacokinetic analysis and TDM in critically ill patients. Additionally, the composition of PB1, PB2, ile-PB1, PE1, and PE2 remains unchanged from 0 to 12 h after entering the patient's body.

Asunto(s)

Antibacterianos , Monitoreo de Drogas , Polimixina B , Espectrometría de Masas en Tándem , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antibacterianos/farmacocinética , Antibacterianos/sangre , Calibración , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Colistina/farmacocinética , Colistina/sangre , Colistina/análogos & derivados , Enfermedad Crítica , Monitoreo de Drogas/métodos , Límite de Detección , Polimixina B/farmacocinética , Polimixina B/sangre , Polimixinas/farmacocinética , Polimixinas/sangre , Polimixinas/análogos & derivados , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodos

RESUMEN

Tyrosine kinase inhibitors (TKIs) and triazole antifungals are the first-line drugs for treating chronic myeloid leukemia (CML) and fungal infections, respectively, but both suffer from large exposure differences and narrow therapeutic windows. Moreover, these two types of drugs are commonly used together in CML patients with fungal infections. Multiple studies and guidelines have suggested the importance of therapeutic drug monitoring (TDM) of TKIs and triazoles. Currently, methods for the simultaneous determination of both types of drugs are limited. We developed a simple, rapid, and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of three commonly used TKIs (imatinib, dasatinib, and nilotinib) and three commonly used triazoles (voriconazole, itraconazole, and posaconazole) in human plasma. The analytes were eluted on a Welch XB-C18 analytical column (50 × 2.1 mm, 5 µm) at 0.7 mL/min, using a gradient elution of 10 mM ammonium formate (A) and methanol-acetonitrile-isopropanol (80:10:10, v/v/v) containing 0.2 % formic acid (B) with a total analysis time of 3.5 min. The calibration curves were linear over the range from 20 to 4000 ng/mL for imatinib and nilotinib, from 2 to 400 ng/mL for dasatinib, and from 50 to 10,000 ng/mL for voriconazole, itraconazole, and posaconazole. Selectivity, accuracy, precision, recovery, matrix effect, and stability all met the validation requirements. The method was successfully used for TDM in CML patients who co-treated with both TKIs and triazoles. Drug-drug interaction analysis between TKIs and triazoles showed that a significant positive correlation was observed between imatinib and voriconazole, as well as dasatinib and voriconazole. Therefore, this method can be well applied in clinical TDM for patients receiving TKIs, triazoles, or both simultaneously.

Asunto(s)

Interacciones Farmacológicas , Monitoreo de Drogas , Inhibidores de Proteínas Quinasas , Espectrometría de Masas en Tándem , Triazoles , Humanos , Espectrometría de Masas en Tándem/métodos , Triazoles/sangre , Triazoles/uso terapéutico , Monitoreo de Drogas/métodos , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/química , Reproducibilidad de los Resultados , Cromatografía Liquida/métodos , Modelos Lineales , Límite de Detección , Cromatografía Líquida con Espectrometría de Masas

RESUMEN

Clinical studies investigating the benefits of beta-lactam therapeutic drug monitoring (TDM) among critically ill patients are hindered by small patient groups, variability between studies, patient heterogeneity, and inadequate use of TDM. Accordingly, definitive conclusions regarding the efficacy of TDM remain elusive. To address these challenges, we propose an innovative approach that leverages data-driven methods to unveil the concealed connections between therapy effectiveness and patient data, collected through a randomized controlled trial (DRKS00011159; 10th October 2016). Our findings reveal that machine learning algorithms can successfully identify informative features that distinguish between healthy and sick states. These hold promise as potential markers for disease classification and severity stratification, as well as offering a continuous and data-driven "multidimensional" Sequential Organ Failure Assessment (SOFA) score. The positive impact of TDM on patient recovery rates is demonstrated by unraveling the intricate connections between therapy effectiveness and clinically relevant data via machine learning.

Asunto(s)

Monitoreo de Drogas , Aprendizaje Automático , Sepsis , Humanos , Sepsis/tratamiento farmacológico , Sepsis/diagnóstico , Monitoreo de Drogas/métodos , Masculino , Femenino , Persona de Mediana Edad , Anciano , beta-Lactamas/uso terapéutico , Antibacterianos/uso terapéutico , Algoritmos , Enfermedad Crítica , Puntuaciones en la Disfunción de Órganos

RESUMEN

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as icotinib, osimertinib, and aumolertinib have emerged as promising treatment options for EGFR mutated Non-small cell lung cancer (NSCLC) patients. Additionally, anlotinib, an anti-angiogenic agent targeting VEGFR, FGFR, and PDGFR, has been used in combination with EGFR-TKIs in NSCLC cases. A method utilizing ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and validated for quantifying icotinib, osimertinib, aumolertinib and anlotinib simultaneously in clinical TDM. The chromatographic separation was performed using a Kinetex C18 column (100 mm × 2.1 mm) and an elution gradient of ammonium acetate in water acidified with 0.1 % formic acid and in acetonitrile. The assay was validated over a linear range of 4-2000 ng/mL for icotinib, 2-1000 ng/mL for osimertinib, 1-500 ng/mL for aumolertinib, and 0.8-400 ng/mL for anlotinib, following the guidelines on bioanalytical methods by FDA. The quantification method exhibited satisfactory performance in terms of selectivity, accuracy (from 91.3 % to 107 %), precision (intra- and inter-day coeffficients of variation ranged from 0.944 % to 7.48 %), linearity, recovery (from 86.0 % to 91.9 %), matrix effect (IS-normalized matrix factors were from 96.7 % to 102 %), and stability. Overall, the method proved to be sensitive, reliable, and straightforward, enabling successful simultaneous determination of blood concentrations of icotinib, osimertinib, aumolertinib, and anlotinib in patients. The validity of the method has been confirmed across various instruments.

Asunto(s)

Acrilamidas , Compuestos de Anilina , Éteres Corona , Monitoreo de Drogas , Indoles , Quinazolinas , Quinolinas , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/métodos , Quinolinas/sangre , Quinolinas/uso terapéutico , Quinolinas/farmacocinética , Indoles/sangre , Indoles/farmacocinética , Indoles/uso terapéutico , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Acrilamidas/sangre , Compuestos de Anilina/sangre , Quinazolinas/sangre , Quinazolinas/uso terapéutico , Quinazolinas/farmacocinética , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Reproducibilidad de los Resultados , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacocinética , Pirazinas/sangre , Pirazinas/farmacocinética , Pirazinas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/sangre , Cromatografía Líquida con Espectrometría de Masas , Benzamidas , Pirimidinas

RESUMEN

The thiopurine drugs-azathioprine and mercaptopurine-are purine antimetabolites used for the treatment of autoimmune hepatitis. These drugs undergo metabolism through genetically determined pathways, which influences their effectiveness and toxicity. There is scarce information regarding the clinical effects of measuring drug metabolites in these patients. The goal of the study is to test the clinical significance of measuring thiopurine metabolites in patients unsuccessfully treated with thiopurines. Clinical and laboratory data collected for patients who were treated for autoimmune hepatitis between 2015 and 2018, and did not achieve full remission under thiopurine therapy and had thiopurine metabolite levels measured due to lack of response and suspicious side effects were chosen. We compared clinical and laboratory data before and after the therapy change. The study included 25 tests of thiopurine metabolites in 21 patients. Six tests had therapeutic levels. Three tests showed high levels leading to lowering the drug dose. In 11 cases, levels of 6-thioguanine nucleotide were low; the dose was not changed in 3 of these, and the dose was increased in the remaining 8. Shunting was observed in 5 cases, 2 of which were mild and the dose was not changed. In the remaining 3, the dose was decreased, and allopurinol was added. Significant improvements in liver enzymes were observed following dose adjustments. We showed that, in cases of suboptimal response to thiopurine treatment, measuring thiopurine metabolites had an important role in optimizing therapy. In most patients, changing the dose led to a significant improvement with no need to switch to secondline therapies.

Asunto(s)

Azatioprina , Hepatitis Autoinmune , Inmunosupresores , Mercaptopurina , Humanos , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/metabolismo , Hepatitis Autoinmune/sangre , Femenino , Masculino , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapéutico , Mercaptopurina/metabolismo , Mercaptopurina/sangre , Persona de Mediana Edad , Azatioprina/uso terapéutico , Adulto , Inmunosupresores/uso terapéutico , Anciano , Resultado del Tratamiento , Nucleótidos de Guanina/sangre , Estudios Retrospectivos , Monitoreo de Drogas/métodos , Tionucleótidos/sangre

RESUMEN

Apixaban, a direct oral anticoagulant drug (DOAC), typically does not require routine therapeutic drug monitoring (TDM), yet recent guidelines propose its use in specific clinical scenarios. While various antifactor Xa (anti-FXa) chromogenic assays serve as useful proxies for measuring plasma exposure to apixaban in emergencies, they lack specificity compared with chromatographic methods. This research project is intended to the development and validation of a standardized protocol of liquid chromatography-tandem mass spectrometry (LC-MS/MS) in conformity with the ICH guidelines M10 for the measurement of apixaban in both plasma and dried plasma spots (DPSs). Samples preparation included protein precipitation after the addition of a deuterated internal standard (IS), and the chromatographic separation was carried out on a Thermo Scientific™ Accucore™ Polar Premium column (50 mm × 2.1 mm, i.d. 2.6 m). The newly developed LC-MS/MS method for apixaban mesurement from both plasma and DPS resulted linear over a wide concentration range (31.25-500 ng/mL), accurate, and reproducible without matrix effects, allowing for specific and rapid quantification. Stability was assessed on quality controls and a real sample, allowing the setting up of a robust TDM protocol that was applied to five anonymized plasma samples obtained from adult patients undergoing apixaban treatment at steady-state. In conclusion our novel LC-MS/MS method is adequate for accurate apixaban quantitation from both plasma and DPS matrixes, and may thus facilitate the guidelines suggested implementation of apixaban TDM, even in peripheral hospitals through shipment of DPS at reference laboratories.

Asunto(s)

Pruebas con Sangre Seca , Monitoreo de Drogas , Inhibidores del Factor Xa , Pirazoles , Piridonas , Espectrometría de Masas en Tándem , Piridonas/sangre , Espectrometría de Masas en Tándem/métodos , Humanos , Pirazoles/sangre , Pirazoles/farmacocinética , Monitoreo de Drogas/métodos , Pruebas con Sangre Seca/métodos , Reproducibilidad de los Resultados , Cromatografía Liquida/métodos , Inhibidores del Factor Xa/sangre , Inhibidores del Factor Xa/farmacocinética , Límite de Detección , Modelos Lineales

RESUMEN

Therapeutic drug monitoring (TDM) of imatinib (IM) in cancer therapy offers the potential to improve treatment efficacy while minimizing toxicity. There was a significant correlation between unbound concentration and clinical response and toxicity, compared with total plasma concentrations, and the quantification of unbound IM and its metabolite, N-desmethyl imatinib (NDI) are of interest for TDM. However, traditional unbound drug separation methods have shortcomings, especially are susceptible to non-specific binding (NSB) of drugs to the polymer-constructed components of filter membranes, which are difficult to avoid at present. Hence it is necessary to developed a reliable separation method for the analysis of the unbound fraction of IM and NDI in TDM. We developed and validated an hollow fiber solid phase microextraction (HF-SPME) method coupled with high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) that to measure unbound IM and NDI concentration in human plasma. It used the NSB phenomenon and solve the NSB problem. The preparation procedure only involves a common vortex and ultrasonication without dilution of samples and modification of membrane. A total of 50 chronic myeloid leukemia (CML) patients were enrolled in our study. The relationship between the unbound and total concentrations for IM and NDI, as well as the concentration ratios of NDI to IM in 50 clinical plasma samples were investigated. The extraction recovery is high to 95.5-106 % with validation parameters for the methodological results were all excellent. There were both a poor linear relationship between the unbound and total concentrations for IM (r2=0.504) and NDI (r2=0.201) in 50 clinical plasma samples. The unbound concentration ratios of NDI to IM varied widely in CML patients. The determination of unbound IM and NDI concentration is meaningful and necessary. The developed HF-SPME method is simple, accurate and precise that could be used to measure unbound IM and NDI concentration in clinical TDM.

Asunto(s)

Monitoreo de Drogas , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Microextracción en Fase Sólida , Espectrometría de Masas en Tándem , Humanos , Mesilato de Imatinib/sangre , Mesilato de Imatinib/farmacocinética , Microextracción en Fase Sólida/métodos , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Monitoreo de Drogas/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Femenino , Masculino , Persona de Mediana Edad , Adulto , Reproducibilidad de los Resultados

RESUMEN

Immunosuppressive drugs (ISDs) are given to avoid the allograft rejection after transplantation. The concentrations of ISDs should be closely monitored owing to their wide inter-individual variability in its pharmacokinetics and narrow therapeutic window. Currently, the whole blood concentration measurement is the major approach of therapeutic drug monitoring of clinical ISDs in organ transplantation. Its correlation with the efficacy of ISDs remains elusive. While the acute rejection after transplantation may occur even when whole-blood ISDs concentrations are within the target range. Since the site of action of ISDs are within the lymphocyte, direct measurement of drug exposure in target cells may more accurately reflect the clinical efficacy of ISDs. Although several methods have been developed for the peripheral blood mononuclear cells (PBMCs) extraction and drug concentration measurement, the complex pre-processing has limited the study of the relationship between intracellular ISDs concentrations and the occurrence of rejection. In this study, the extraction of ISDs in PBMCs was carried out by the liquid-liquid extraction with low temperature purification, without centrifugation. The lower limit of quantitation were 0.2 ng/mL for cyclosporine A, tacrolimus and sirolimus, 1.0 ng/mL for mycophenolic acid, and the within-run and between-run coefficient of variations were both less than 12.4 %. The calibration curves of mycophenolic acid had a linear range (ng/mL): 1.0-128.0 (r2 = 0.9992). The calibration curves of other three ISDs had a linear range (ng/mL): 0.2-20.48 (r2 > 0.9956). A total of 157 clinical samples were analyzed by the UPLC-MS/MS for ISDs concentration in blood or plasma ([ISD]blood or plasma) and the concentration within PBMCs ([ISD]PBMC). Although there was strong association between [ISD]PBMC and [ISD]blood or plasma, the large discrepancies between concentration within [ISD]blood or plasma and [ISD]PBMC were observed in a small proportion of clinical samples. The developed method with short analysis time and little amounts of blood sample can be successfully applied to therapeutic drug monitoring of ISDs in PBMCs for analysis of large numbers of clinical samples and is helpful to explore the clinical value of ISDs concentration in PBMCs.

Asunto(s)

Monitoreo de Drogas , Inmunosupresores , Leucocitos Mononucleares , Extracción Líquido-Líquido , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/métodos , Extracción Líquido-Líquido/métodos , Inmunosupresores/sangre , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Tacrolimus/sangre , Ácido Micofenólico/sangre , Ácido Micofenólico/farmacocinética , Ciclosporina/sangre , Reproducibilidad de los Resultados , Límite de Detección , Sirolimus/sangre , Cromatografía Líquida con Espectrometría de Masas

RESUMEN

The optimal frequency and timing of laboratory monitoring during isotretinoin treatment remains controversial. We aimed to investigate the frequency, timing, and severity of abnormal results during isotretinoin for acne. We conducted a retrospective cohort study comprising 444 acne patients prescribed isotretinoin at Boston Medical Center from 2004 to 2017; these patients had at least one available baseline laboratory result. We categorized patients into two groups: group A (normal values at baseline and during the first 2 months of isotretinoin therapy) and group B (abnormal values at baseline or during the first 2 months of isotretinoin therapy) and assessed the laboratory values after 2 months. The frequency of abnormal results for triglycerides, cholesterol, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) after 2 months for patients in group A was 21.1%, 13.6%, 8.8%, and 6.0%, respectively, with very rare grade 2 (moderate) or higher abnormalities. In contrast, the frequency of abnormal results for patients in group B for triglycerides, cholesterol, AST, and ALT was higher at 67.9%, 88.0%, 40.0%, and 25.0%, respectively (P < 0.05, except for ALT). No patient developed higher than grade 1 (mild) complete blood count (CBC) abnormality. This study proposed that healthy patients with normal results at baseline and during the first 2 months of isotretinoin therapy might not need routine monitoring after month 2 of medication. Routine monitoring of CBC is not necessary.

Asunto(s)

Acné Vulgar , Alanina Transaminasa , Aspartato Aminotransferasas , Fármacos Dermatológicos , Isotretinoína , Humanos , Isotretinoína/uso terapéutico , Isotretinoína/efectos adversos , Isotretinoína/administración & dosificación , Acné Vulgar/tratamiento farmacológico , Estudios Retrospectivos , Masculino , Fármacos Dermatológicos/uso terapéutico , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/efectos adversos , Femenino , Alanina Transaminasa/sangre , Adulto Joven , Aspartato Aminotransferasas/sangre , Adolescente , Adulto , Triglicéridos/sangre , Colesterol/sangre , Factores de Tiempo , Monitoreo de Drogas/métodos