RESUMEN

Cancer remains one of the leading causes for death worldwide. Palliative chemotherapy is vital for certain cancer patients, highlighting the critical need for treatment monitoring tools to prevent drug accumulation and mitigate the risk of high toxicity. Therefore, our aim was to evaluate the potential of screen-printed electrodes for the development of sensitive and accurate biosensors for the detection/quantification of antineoplastic drugs. To this purpose, we developed a cisplatin sensor. By functionalizing the gold electrode with human serum albumin and by collecting the electrochemical signal obtained in a H2O2 solution, through voltammetry measurements, we were able to correlate the current measured at 430 mV with the concentration of cisplatin present in human serum samples, with a correlation coefficient of R2 = 0.99. Also, a bleomycin biosensor was developed and proven functional, but further optimization steps were employed in order to improve the accuracy. The developed biosensors have a detection range of 0.0006-43.2 mg/mL for cisplatin and 0.23-7.56 µg/mL for bleomycin in the serum samples. Our preliminary results show that these biosensors can facilitate the real-time monitoring of cisplatin and bleomycin serum levels, allowing healthcare professionals to tailor treatment strategies based on individual patient responses.

Asunto(s)

Antineoplásicos , Técnicas Biosensibles , Bleomicina , Cisplatino , Electrodos , Bleomicina/sangre , Cisplatino/sangre , Humanos , Técnicas Biosensibles/métodos , Antineoplásicos/sangre , Antineoplásicos/análisis , Albúmina Sérica Humana/análisis , Técnicas Electroquímicas/métodos , Oro/química

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

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

OBJECTIVE: The aim of this study was to establish a simple and sensitive high-performance liquid chromatography method for therapeutic drug monitoring of venetoclax (VEN) and optimize regimens. METHODS: The analysis required the extraction of a 50 µl plasma sample and the precipitation of proteins using acetonitrile extraction. The chromatographic method employed a mobile phase of acetonitrile: 0.5% KH 2 PO 4 (pH 3.5) (60/40, v/v) on a Diamond C 18 (4.6 mm × 250 mm, 5 µm) column at a flow rate of 1.0 ml/min. The quantitative method was validated based on standards described in 'Bioanalytical Method Validation: Guidance for Industry' published by the US Food and Drug Administration (FDA). RESULTS: The calibration curve was linear ( R2  = 0.9998) over the range of 75-4800 ng/ml, with limits of quantification of 25 ng/ml. The coefficients of intraday and interday validation, specificity, recovery, and stability all met the criteria of FDA guidance. The method was successfully applied to analyze VEN concentrations in 30 cases of acute myeloid leukemia patients. The peak concentration ( Cmax ) was 1881.19 ±â€…756.61 ng/ml, while the trough concentration ( Cmin ) was 1212.69 ±â€…767.92 ng/ml in acute myeloid leukemia patients. CONCLUSION: Our study establishes a simple, precise, and sensitive high-performance liquid chromatography method for monitoring VEN and confirms its applicability for therapeutic drug monitoring of VEN in hematological cancers.

Asunto(s)

Compuestos Bicíclicos Heterocíclicos con Puentes , Monitoreo de Drogas , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/sangre , Sulfonamidas/sangre , Sulfonamidas/farmacocinética , Sulfonamidas/administración & dosificación , Monitoreo de Drogas/métodos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/sangre , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Cromatografía Líquida de Alta Presión/métodos , Masculino , Persona de Mediana Edad , Femenino , Adulto , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Anciano , Medicina de Precisión/métodos , Adulto Joven , China , Pueblos del Este de Asia

RESUMEN

BACKGROUND AND OBJECTIVE: Trough abiraterone concentration (ABI Cmin) of 8.4 ng/mL has been identified as an appropriate efficacy threshold in patients treated for metastatic castration-resistant prostate cancer (mCRPC). The aim of the phase II OPTIMABI study was to evaluate the efficacy of pharmacokinetics (PK)-guided dose escalation of abiraterone acetate (AA) in underexposed patients with mCRPC with early tumour progression. METHODS: This multicentre, non-randomised study consisted of two sequential steps. In step 1, all patients started treatment with 1000 mg of AA once daily. Abiraterone Cmin was measured 22-26 h after the last dose intake each month during the first 12 weeks of treatment. In step 2, underexposed patients (Cmin < 8.4 ng/mL) with tumour progression within the first 6 months of treatment were enrolled and received AA 1000 mg twice daily. The primary endpoint was the rate of non-progression at 12 weeks after the dose doubling. During step 1, adherence to ABI treatment was assessed using the Girerd self-reported questionnaire. A post-hoc analysis of pharmacokinetic (PK) data was conducted using Bayesian estimation of Cmin from samples collected outside the sampling guidelines (22-26 h). RESULTS: In the intention-to-treat analysis (ITT), 81 patients were included in step 1. In all, 21 (26%) patients were underexposed in step 1, and 8 of them (38%) experienced tumour progression within the first 6 months. A total of 71 patients (88%) completed the Girerd self-reported questionnaire. Of the patients, 62% had a score of 0, and 38% had a score of 1 or 2 (minimal compliance failure), without a significant difference in mean ABI Cmin in the two groups. Four patients were enrolled in step 2, and all reached the exposure target (Cmin > 8.4 ng/mL) after doubling the dose, but none met the primary endpoint. In the post-hoc analysis of PK data, 32 patients (39%) were underexposed, and ABI Cmin was independently associated with worse progression-free survival [hazard ratio (HR) 2.50, 95% confidence interval (CI) 1.07-5.81; p = 0.03], in contrast to the ITT analysis. CONCLUSION: The ITT and per-protocol analyses showed no statistical association between ABI underexposure and an increased risk of early tumour progression in patients with mCRPC, while the Bayesian estimator showed an association. However, other strategies than dose escalation at the time of progression need to be evaluated. Treatment adherence appeared to be uniformly good in the present study. Finally, the use of a Bayesian approach to recover samples collected outside the predefined blood collection time window could benefit the conduct of clinical trials based on drug monitoring. OPTIMABI trial is registered as National Clinical Trial number NCT03458247, with the EudraCT number 2017-000560-15).

Asunto(s)

Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/patología , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Androstenos/administración & dosificación , Androstenos/farmacocinética , Androstenos/uso terapéutico , Acetato de Abiraterona/administración & dosificación , Acetato de Abiraterona/farmacocinética , Acetato de Abiraterona/uso terapéutico , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antineoplásicos/sangre , Metástasis de la Neoplasia

RESUMEN

Interest is increasing in the use of different liquid chromatography techniques coupled online to mass spectrometry for the quantification of platinum anticancer drugs in human plasma to inform cancer chemotherapy. We developed, validated and studied the application of a method for quantification of intact oxaliplatin in human plasma using ultra high performance liquid chromatography hyphenated to inductively coupled plasma mass spectrometry (UHPLC-ICP-MS). Plasma samples were processed instantly after collection from patients to preserve oxaliplatin speciation by methanol-deproteinization, and storage of diluted supernatants (plasma:methanol 1:2 v/v) at -80 °C. UHPLC separation of intact oxaliplatin and internal standard (carboplatin) was achieved using a C18 column and linear gradient mobile phase (Mobile phase A: water-methanol (97:3 v/v), 0.075 mM sodium dodecyl sulfate, 9.79 nM thallium adjusted to pH 2.5 with trifluoromethanesulfonic acid; Mobile phase B: 100 % methanol (v/v)) with ICP-MS detection to monitor platinum and thallium at m/z 195 and 205, respectively. The limit of quantification was 50 nM in methanol-deproteinized diluted plasma (1:2 v/v). Linearity was established for calibration standards ranging from 50 to 500 nM made in methanol-deproteinized diluted plasma (1:2 v/v), and for dilution of higher concentration samples in blank matrix containing internal standard (final dilution 1:29 v/v). Intra-day and inter-day accuracy ranged from 96.8 to 103 % of nominal concentration and precision from 0.62 to 2.49 % coefficient of variation. Recovery was complete and a matrix effect confirmed the requirement for matrix-matched standards. Intact oxaliplatin was stable during storage for at least 473 days, and during analysis, in methanol-deproteinized diluted plasma (1:2 v/v). The method was applied to determining the plasma concentrations of intact oxaliplatin in patients undergoing cancer chemotherapy, and studies of oxaliplatin degradation in vitro. This improved method based on UHPLC-ICP-MS will allow more specific, efficient and reliable quantification of intact oxaliplatin in human plasma.

Asunto(s)

Límite de Detección , Espectrometría de Masas , Oxaliplatino , Humanos , Oxaliplatino/sangre , Oxaliplatino/química , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas/métodos , Reproducibilidad de los Resultados , Antineoplásicos/sangre , Antineoplásicos/química , Antineoplásicos/análisis , Modelos Lineales , Compuestos Organoplatinos/sangre , Compuestos Organoplatinos/química

RESUMEN

This study aimed to establish a population pharmacokinetic (PopPK) model using data from 2 clinical trials of zimberelimab, evaluate the pharmacokinetics (PKs) of zimberelimab, explore the feasibility of 360 mg once every 3 weeks (Q3W) and 480 mg once every 4 weeks (Q4W) as alternative dosage regimens, and analyze the exposure-response relationship of the efficacy and safety of zimberelimab for advanced tumors. The PKs of zimberelimab were described using the 2-compartment model with time-dependent nonlinear elimination. The prediction-corrected visual predictive check was used to evaluate the model's predictive value on blood drug concentrations. In total, 2165 PK observations from 321 participants were included. The PopPK model demonstrated a high level of concordance between the observed data and the predicted values, indicative of a robust fit to the PK data of zimberelimab. The PK variables were similar for the 240 mg once every 2 weeks, 360 mg Q3W, and 480 mg Q4W regimens. No covariates significantly affecting the PK variables in the final model were found. The exposure variables of zimberelimab have no obvious correlations with efficacy and safety, and 360 mg Q3W and 480 mg Q4W are worthy of further study. This study establishes a PopPK model and analyzes the exposure-response relationship of zimberelimab, which helps to explore the potential for alternative dosing regimens and offers a foundation for optimizing therapeutic strategies for advanced cancer patients through simulation-based methods.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Pueblo Asiatico , Relación Dosis-Respuesta a Droga , Modelos Biológicos , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Esquema de Medicación , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Adulto Joven , China , Pueblos del Este de Asia

RESUMEN

A novel and robust electrochemical sensing tool for the determination of vismodegib (VIS), an anticancer drug, has been developed by integrating the selective recognition capabilities of molecularly imprinted polymer (MIP) and the sensitivity enhancement capability of metal-organic framework (MOF). Prior to this step, the electrochemical behavior of VIS was investigated using a bare glassy carbon electrode (GCE). It was observed that in 0.5 M H2SO4 solution as electrolyte, VIS has an oxidation peak around 1.3 V and the oxidation mechanism is diffusion controlled. The determination of VIS in a standard solution using a bare GCE showed a linear response in the concentration range from 2.5 µM to 100 µM, with a limit of detection (LOD) of 0.75 µM. Since sufficient sensitivity and selectivity could not be achieved with bare GCE, a MIP sensor was developed in the next step of the study. For this purpose, the GCE surface was first modified by drop casting with as-synthesized Co-MOF. Subsequently, a MIP network was synthesized via a thermal polymerization approach using 2-acrylamido-2-methylpropanesulfonic acid (AMPS) as monomer and VIS as template. MOFs are ideal electrode materials due to their controllable and diverse morphologies and modifiable surface properties. These characteristics enable the development of MIPs with more homogeneous binding sites and high affinity for target molecules. Integrating MOFs could help the performance of sensors with the desired stability and reproducibility. Electrochemical analysis revealed an observable enhancement of the output signal by the incorporation of MOF molecules, which is consistent with the sensitivity-enhancing role of MOF by providing more anchoring sites for the attachment of the polymer texture to the electrode surface. This MOF-MIP sensor exhibited impressive linear dynamic ranges ranging from 0.1 to 1.0 pM for VIS, with detection limits in the low picomolar range. In addition, the MOF-MIP sensor offers high accuracy, selectivity and precision for the determination of VIS, with no interference observed from complex media of serum samples. Additionally, in this study, Analytical GREEnness metric (AGREE), Analytical GREEnness preparation (AGREEprep) and Blue Applicability Grade Index (BAGI) were used to calculate the green profile score.

Asunto(s)

Anilidas , Antineoplásicos , Técnicas Electroquímicas , Electrodos , Estructuras Metalorgánicas , Polímeros Impresos Molecularmente , Piridinas , Estructuras Metalorgánicas/química , Polímeros Impresos Molecularmente/química , Piridinas/química , Técnicas Electroquímicas/métodos , Antineoplásicos/análisis , Antineoplásicos/química , Antineoplásicos/sangre , Anilidas/química , Anilidas/análisis , Anilidas/sangre , Límite de Detección , Impresión Molecular , Polímeros/química

RESUMEN

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6ß-hydroxycortisol, deoxycholic acid, and 1ß-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.

Asunto(s)

Biomarcadores , Citocromo P-450 CYP3A , Monitoreo de Drogas , Compuestos de Fenilurea , Quinolinas , Humanos , Compuestos de Fenilurea/orina , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/sangre , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Femenino , Quinolinas/orina , Quinolinas/uso terapéutico , Quinolinas/sangre , Quinolinas/administración & dosificación , Quinolinas/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Anciano , Persona de Mediana Edad , Masculino , Biomarcadores/orina , Biomarcadores/sangre , Monitoreo de Drogas/métodos , Adulto , Anciano de 80 o más Años , Antineoplásicos/orina , Antineoplásicos/uso terapéutico , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Inhibidores de Proteínas Quinasas/orina , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Neoplasias/tratamiento farmacológico , Neoplasias/sangre , Neoplasias/orina , Espectrometría de Masas en Tándem/métodos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/orina , Neoplasias Endometriales/sangre , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/orina , Cromatografía Liquida/métodos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/orina , Neoplasias de la Tiroides/sangre , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/orina , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/orina , Carcinoma de Células Renales/sangre

RESUMEN

Quantification of the unbound portion of platinum (Pt) in human plasma is important for assessing the pharmacokinetics of the chemotherapeutic drug cisplatin. In this study, we sought to compare the recovery of unbound Pt using Nanosep® filters to 1) traditional filters (Centrifree®, Centrisart®, Amicon®) or trichloroacetic acid (TCA) protein precipitation, and 2) unbound, bound, and total Pt concentrations in clinical specimens. For the tested filters, the impact of 1) molecular weight cut-offs, 2) centrifugation force, and 3) total Pt concentration on Pt binding in human plasma was evaluated. Pt was quantified using inductively coupled-plasma mass spectrometry. In human plasma spiked with 0.9 µg/mL Pt, the percent of unbound Pt increased at higher centrifugation speeds. By comparison, the percent of unbound Pt was highest (42.1%) following TCA protein precipitation. When total Pt was ≤0.9 µg/mL, unbound Pt (∼20-30%) was consistent across filters. Conversely, when plasma was spiked with Pt exceeding 0.9 µg/mL, the percent of unbound Pt increased from 36.5 to 48% using ultrafiltration, compared to 63.4% to 79% with TCA precipitation. In patients receiving cisplatin-containing chemotherapy, the fraction of unbound Pt at concentrations exceeding 0.9 µg/mL ranged between 35 and 90%. Moreover, the unbound fraction of Pt in plasma correlated with the concentration of unbound (R2 = 0.738) and total Pt (R2 = 0.335). In summary, this study demonstrates that 1) the percent of unbound Pt is influenced by total and unbound Pt levels in vitro and in clinical specimens, and 2) ultrafiltration with Nanosep® filters is a feasible method for quantifying unbound Pt concentrations in human plasma.

Asunto(s)

Precipitación Química , Cisplatino , Ultrafiltración , Humanos , Ultrafiltración/métodos , Cisplatino/sangre , Cisplatino/farmacocinética , Platino (Metal)/sangre , Platino (Metal)/farmacocinética , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Unión Proteica , Ácido Tricloroacético/sangre

RESUMEN

In this study, a magnetic three-dimensional nano-composite based on Rubber-Fe3O4@Ni-Co Layered double hydroxide derived from ZIF-67 template was synthesized by a hydrothermal method. The proposed nano-composite was used as a sorbent for the enrichment of trace amounts of anti-cancer drugs (dasatinib and erlotinib hydrochloride) from plasma samples followed by determination using high-performance liquid chromatographic analysis (HPLC-UV). The synthesized nano-sorbent was characterized by X-ray diffraction, field emission scanning electron microscopy, Fourier transform infrared spectroscopy, vibrating-sample magnetometer, Brunauer-Emmett-Teller surface analysis, Barrett-Joyner-Halenda pore size analysis and energy dispersive X-ray spectroscopy. Under optimal experimental conditions, factors affecting on extraction efficiency such as pH, ionic strength, extraction temperature and time, desorption solvent and time, the limit of detection (LODs) and the limit of quantification (LOQs) were obtained as 0.6, 2 µg/L for both of dasatinib and erlotinib, respectively. Also, linear range of the method were 2-500 and 2-1000 µg/L for dasatinib and erlotinib, respectively. Relative standard deviations (RSD%) for the repeatability of extraction on sorbent to sorbent were obtained as 3.59, 1.97 %, and one sorbent reusability were investigated and relative standard deviation values were obtained 5.35, 3.30 % for dasatinib and erlotinib, respectively.

Asunto(s)

Antineoplásicos , Clorhidrato de Erlotinib , Límite de Detección , Goma , Goma/química , Antineoplásicos/sangre , Antineoplásicos/química , Cromatografía Líquida de Alta Presión/métodos , Reproducibilidad de los Resultados , Humanos , Clorhidrato de Erlotinib/sangre , Clorhidrato de Erlotinib/química , Modelos Lineales , Dasatinib/sangre , Dasatinib/química , Hidróxidos/química , Imidazoles/química , Imidazoles/sangre , Adsorción , Extracción en Fase Sólida/métodos , Cobalto/química , Cobalto/sangre , Nanoestructuras/química , Zeolitas

RESUMEN

The purpose of this study was to develop and validate a physiologically based pharmacokinetic (PBPK) model combined with an EGFR occupancy (EO) model for osimertinib (OSI) to predict plasma trough concentration (Ctrough) and the intracranial time-course of EGFR (T790M and L858R mutants) engagement in patient populations. The PBPK model was also used to investigate the key factors affecting OSI pharmacokinetics (PK) and intracranial EGFR engagement, analyze resistance to the target mutation C797S, and determine optimal dosing regimens when used alone and in drug-drug interactions (DDIs). A population PBPK-EO model of OSI was developed using physicochemical, biochemical, binding kinetic, and physiological properties, and then validated using nine clinical PK studies, observed EO study, and two clinical DDI studies. The PBPK-EO model demonstrated good consistency with observed data, with most prediction-to-observation ratios falling within the range of 0.7 to 1.3 for plasma AUC, Cmax, Ctrough and intracranial free concentration. The simulated time-course of C797S occupancy by the PBPK model was much lower than T790M and L858R occupancy, providing an explanation for OSI on-target resistance to the C797S mutation. The PBPK model identified ABCB1 CLint,u, albumin level, and EGFR expression as key factors affecting plasma Ctrough and intracranial EO for OSI. Additionally, PBPK-EO simulations indicated that the optimal dosing regimen for OSI in patients with brain metastases is either 80 mg once daily (OD) or 160 mg OD, or 40 mg or 80 mg twice daily (BID). When used concomitantly with CYP enzyme perpetrators, the PBPK-EO model suggested appropriate dosing regimens of 80 mg OD with fluvoxamine (FLUV) itraconazole (ITR) or fluvoxamine (FLUC) for co-administration and an increase to 160 mg OD with rifampicin (RIF) or efavirenz (EFA). In conclusion, the PBPK-EO model has been shown to be capable of simulating the pharmacokinetic concentration-time profiles and the time-course of EGFR engagement for OSI, as well as determining the optimum dosing in various clinical situations.

Asunto(s)

Acrilamidas , Compuestos de Anilina , Neoplasias Encefálicas , Receptores ErbB , Humanos , Compuestos de Anilina/farmacocinética , Compuestos de Anilina/administración & dosificación , Acrilamidas/farmacocinética , Acrilamidas/administración & dosificación , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Modelos Biológicos , Mutación , Femenino , Masculino , Interacciones Farmacológicas , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/sangre , Antineoplásicos/administración & dosificación , Persona de Mediana Edad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Indoles , Pirimidinas

RESUMEN

Therapeutic drug monitoring of pegylated L-asparaginase (ASNase) ensures the drug effectiveness in childhood acute lymphoblastic leukaemia (ALL) patients. The biological drug property with variable immunogenic host clearance, and the prescription of its generic formulation urge the need for a reliable assay to ensure an optimal treatment and improve outcome. This study aimed to optimise an existing isocratic reversed-phase high performance liquid chromatography (RP-HPLC) method with an automated pre-column sample derivatisation and injection program, and a computational algorithm for measuring serum pegylated ASNase activity in children with ALL. Nath et al.'s method in 2009 was adopted and modified using a pegylated ASNase. A set of Microsoft Excel macros was developed for the serum drug activity computation. An Agilent InfinityLab LC Series 1260 Infinity II Quaternary System with fluorescence detection was employed with an Agilent Poroshell 120 EC-C18 4.6×100 mm, 2.7 µm analytical column. System flow rate was optimised to 2.0 mL/min with 40×10-6/bar pump compressibility. The O-phthaldialdehyde (OPA) solution composition was optimised to 1 % o-phthaldialdehyde, 0.8 % 2-mercaptoethanol, 7.13 % methanol, and 1.81 % sodium tetraborate. The pre-column derivatisation program mixed 0.1 µL sample with 25 µL OPA solution before the automated injection. Method validation was according to the ICH guidelines. Total analysis time was 15 min, with L-aspartic acid eluted at 0.96 min and internal standard at 4.7 min. The calibration curves showed excellent linearity (R ≥0.9999). Interday precision for the drug activity at 0.1 IU/mL, 0.5 IU/mL, and 1 IU/mL were 4.15 %, 3.05 %, and 3.09 % (n = 6). Mean %error for the drug activity at 0.1 IU/mL, 0.5 IU/mL, and 1 IU/mL were 0.90±4.41 %, -1.37±3.04 %, and -3.03±3.02 % (n = 6). Limit of quantitation was 0.03 IU/mL. Majority of the patients' serum drug activity fell within the assay calibration range. Our improved method is automated, having shorter analysis time with a well-maintained separation resolution that enables a high-throughput analysis for application.

Asunto(s)

Asparaginasa , Monitoreo de Drogas , Polietilenglicoles , Leucemia-Linfoma Linfoblástico de Células Precursoras , Asparaginasa/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Humanos , Cromatografía Líquida de Alta Presión/métodos , Niño , Polietilenglicoles/química , Monitoreo de Drogas/métodos , Antineoplásicos/sangre , Reproducibilidad de los Resultados , Cromatografía de Fase Inversa/métodos , Calibración

RESUMEN

Docetaxel is one of the most effective and safe chemotherapy drugs according to the World Health Organization, but its clinical use has been discontinued due to its various side effects. To reduce these side effects, the amount of docetaxel drug should be kept at the most effective level, it should be monitored in body fluids. Due to the limitations of traditional analytical methods used for this purpose, such as expensive and low sensitivity, labor-intensive and time-consuming complex preliminary preparation, efficient methods are required for the determination of the docetaxel level in the body. The increasing demand for the development of personalized therapy has recently spurred significant research into biosensors for the detection of drugs and other chemical compounds. In this study, an electrochemical-based portable nanobiosensor system was developed for the rapid, low-cost, and sensitive determination of docetaxel. In this context, mg-p(HEMA)-IMEO nanoparticles to be used as nanobiosensor bioactive layer was synthesized, characterized, and docetaxel determination conditions were optimized. According to the results obtained, the developed nanobiosensor system can detect docetaxel with a sensitivity of 2.22 mg/mL in a wide calibration range of 0.25-10 mg/mL, in only 15 min, in mixed media such as commercially available artificial blood serum and urine. determined. We concluded that the developed nanobiosensor system can be successfully used in routine drug monitoring as a low-cost biomedical device capable of direct, rapid, and specific drug determination within the scope of personalized treatment, providing point-of-care testing.

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Therapeutic drug monitoring on-site has the potential to significantly save healthcare expenditures while also improving patient outcomes.Chromatography's applicability as a routine procedure is restricted by its lack of standardization, expensive equipment, lengthy turnaround times, and labor-intensive sample preparation.Overcoming these drawbacks, nanobiosensors provide an inexpensive, user-friendly, on-site analytical approach to fully explore the possibilities of therapeutic drug monitoring.

Asunto(s)

Antineoplásicos , Técnicas Biosensibles , Docetaxel , Monitoreo de Drogas , Nanopartículas , Neoplasias , Medicina de Precisión , Docetaxel/farmacología , Docetaxel/química , Monitoreo de Drogas/instrumentación , Monitoreo de Drogas/métodos , Técnicas Biosensibles/instrumentación , Humanos , Neoplasias/tratamiento farmacológico , Antineoplásicos/sangre , Nanopartículas/química , Nanotecnología , Técnicas Electroquímicas/instrumentación , Técnicas Electroquímicas/métodos

RESUMEN

Letrozole is an anticancer medication prescribed for the management of estrogen receptor-positive breast cancer in postmenopausal women. Chronic pain is prevalent in patients receiving chemotherapy, leading to the use of adjuvant analgesics such as tramadol. This work introduces the first analytical approach for the concurrent quantification of letrozole and tramadol, two co-administered drugs, employing a rapid, highly sensitive, eco-friendly, and cost-effective first derivative synchronous spectrofluorimetric technique. The fluorescence of tramadol and letrozole was measured at wavelengths of 235.9 nm and 241.9 nm, respectively using a wavelength difference (Δλ) of 60.0 nm. The developed approach demonstrated exceptional linearity (r ˃ 0.999) within the specified concentration ranges for tramadol (10.0-1200.0 ng/mL) and letrozole (1.0-140.0 ng/mL). The results demonstrated that the proposed technique exhibits a high level of sensitivity, with detection limits of 0.569 and 0.143 ng/mL for tramadol and letrozole, respectively, indicating the good bioanalytical applicability. The within-run precisions, both intra-day and inter-day, for both analytes, were less than 0.71 % RSD. The developed approach was effectively applied to simultaneously estimate the mentioned drugs in their tablets and human plasma samples, achieving high percentage recoveries and low % RSD values. In order to assess the environmental sustainability of the developed approach, Analytical GREEnnessNNESS (AGREE) and the Green Analytical Procedure Index (GAPI) metric tools were employed. Both tools revealed that the developed approach is excellent green, suggesting its usage as an environmentally-friendly alternative for the routine assayof the investigated pharmaceuticals. The developed approach was validated according to the ICHQ2 (R1) requirements.

Asunto(s)

Neoplasias de la Mama , Letrozol , Límite de Detección , Espectrometría de Fluorescencia , Tramadol , Letrozol/sangre , Letrozol/análisis , Letrozol/administración & dosificación , Tramadol/sangre , Tramadol/análisis , Humanos , Espectrometría de Fluorescencia/métodos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/sangre , Femenino , Antineoplásicos/sangre , Antineoplásicos/análisis , Reproducibilidad de los Resultados , Comprimidos

RESUMEN

AIMS: Therapeutic drug monitoring (TDM) has led to significant improvements in individualized medical care, although its implementation in oncology has been limited to date. Tyrosine kinase inhibitors (TKIs) are a group of therapies for which TDM has been suggested. Osimertinib is one such therapy used in the treatment of epidermal growth factor receptor (EGFR) mutation-driven lung cancer. Herein, we describe a prospective pilot study involving 21 patients on osimertinib primarily as a preliminary evaluation of drug levels in a real-world setting. METHODS: Concentrations of the drug and its primary metabolites were measured with a validated liquid chromatography-mass spectrometry (LC-MS) assay across serial timepoints. As part of this study, inter-individual variability by dose and ethnicity as well as intra-individual variability across timepoints are explored. Furthermore, we attempted to validate dried blood spot (DBS)-based quantitation as an accurate alternative to plasma quantitation. RESULTS: Successful quantitation of osimertinib and primary metabolites was achieved for our subjects. Compound plasma levels were highly correlated to DBS levels. There was no significant difference in concentrations with ethnicity or dosing or intra-individual variability across timepoints. CONCLUSIONS: As such, we demonstrate that TDM for osimertinib is practical for future trials. We also validated the use of DBS as an alternative to conventional quantitation for exploration of TDM for osimertinib in larger trials and for other targeted therapies.

Asunto(s)

Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Pruebas con Sangre Seca , Monitoreo de Drogas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Inhibidores de Proteínas Quinasas , Humanos , Compuestos de Anilina/sangre , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/farmacocinética , Acrilamidas/sangre , Acrilamidas/uso terapéutico , Proyectos Piloto , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangre , Monitoreo de Drogas/métodos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Pruebas con Sangre Seca/métodos , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacocinética , Cromatografía Liquida/métodos , Anciano de 80 o más Años , Adulto , Indoles , Pirimidinas

RESUMEN

Therapeutic drug monitoring (TDM) serves as a potent tool for adjusting drug concentration within a reasonable range. However, continuous monitoring of anticancer drugs in-vivo presents a significant challenge. Herein, we propose a needle-in-needle electrochemical sensor based on an acupuncture needle electrode, capable of monitoring the anticancer drug etoposide in the peritoneal cavity of living rats. The acupuncture needle was modified with Au nanoparticles and etoposide-templated molecularly imprinted polymer (MIP), resulting in high sensitivity and selectivity in the electrochemical detection of etoposide. The modified acupuncture needle (0.16 mm diameter) was anchored inside a syringe needle (1.40 mm diameter), allowing the outer syringe needle to protect the modified materials of the inner acupuncture needle during skin piercing. Due to the unique needle-in-needle design, high stability was obtained during in-vivo etoposide monitoring. Connecting to a smartphone-controlled portable electrochemical workstation, the needle-in-needle sensor offers great convenience in point-of-care TDM. Moreover, the electrode materials on the acupuncture needle were carefully characterized and optimized. Under the optimized conditions, low detection limits and wide linear range were achieved. This work provides new insights into acupuncture needle electrochemical sensors and further expands the feasibility for real-time and in-vivo detection.

Asunto(s)

Técnicas Biosensibles , Monitoreo de Drogas , Etopósido , Oro , Agujas , Etopósido/análisis , Etopósido/administración & dosificación , Animales , Ratas , Técnicas Biosensibles/instrumentación , Oro/química , Monitoreo de Drogas/instrumentación , Técnicas Electroquímicas/métodos , Antineoplásicos/análisis , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Nanopartículas del Metal/química , Polímeros Impresos Molecularmente/química , Límite de Detección , Electrodos , Ratas Sprague-Dawley , Diseño de Equipo

RESUMEN

Daratumumab, a pivotal treatment for multiple myeloma, exhibits considerable inter-patient variability in pharmacological clinical outcomes, likely attributed to serum concentration that may underscore the need for its therapeutic drug monitoring. This study aims to develop and validate a straightforward analytical method for quantifying daratumumab in serum, focusing on intact light chain determination, using liquid chromatography high-resolution mass spectrometry. The sample preparation involved immunoglobulin enrichment using Melon gel followed by a reduction step to dissociate the light from the heavy chains of immunoglobulins. The latter were then separated using a MabPac RP 2.1 × 50 mm chromatographic column and the intact light chains were detected and quantified using a Q Exactive Orbitrap mass spectrometer operating in ESI-positive ion mode at 17 500 resolution. The method demonstrated excellent linearity (R2 > 0.992) across a serum concentration range of 100 to 2000 µg mL-1 and good precision and accuracy: intra- and interday relative errors ranged from -5.1% to 6.5%, with a relative standard deviation of less than 5.8%. Clinical suitability was confirmed by analyzing 80 clinical samples from multiple myeloma patients treated with 1800 mg of daratumumab. 99% of the samples fell within the analytical range with a mean daratumumab concentration evaluated before the next administration (Ctrough) of 398 µg mL-1. These findings highlighted that intact light chain monoclonal antibody quantification could be a valid and robust alternative to either immunoassays or to LC-MS/MS targeting peptides for measuring daratumumab in clinical samples, positioning it as a suitable method for therapeutic drug monitoring applications.

Asunto(s)

Anticuerpos Monoclonales , Monitoreo de Drogas , Cadenas Ligeras de Inmunoglobulina , Mieloma Múltiple , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacocinética , Humanos , Monitoreo de Drogas/métodos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/sangre , Cadenas Ligeras de Inmunoglobulina/sangre , Cromatografía Liquida/métodos , Espectrometría de Masas/métodos , Reproducibilidad de los Resultados , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacocinética , Cromatografía Líquida de Alta Presión/métodos

RESUMEN

BACKGROUND: Letrozole, an aromatase inhibitor metabolised via CYP2A6 and CYP3A4/5 enzymes, is used as adjuvant therapy for women with hormone receptor (HR)-positive early breast cancer. The objective of this study was to quantify the impact of CYP2A6 genotype on letrozole pharmacokinetics (PK), to identify non-adherent patients using a population approach and explore the possibility of a relationship between non-adherence and early relapse. METHODS: Breast cancer patients enrolled in the prospective PHACS study (ClinicalTrials.gov NCT01127295) and treated with adjuvant letrozole 2.5 mg/day were included. Trough letrozole concentrations (Css,trough) were measured every 6 months for 3 years by a validated LC-MS/MS method. Concentration-time data were analysed using non-linear mixed effects modelling. Three methods were evaluated for identification of non-adherent subjects using the base PK model. RESULTS: 617 patients contributing 2534 plasma concentrations were included and led to a one-compartment PK model with linear absorption and elimination. Model-based methods identified 28 % of patients as non-adherent based on high fluctuations of their Css,trough compared to 3 % based on patient declarations. The covariate analysis performed in adherent subjects revealed that CYP2A6 intermediate (IM) and slow metabolisers (SM) had 21 % (CI95 % = 12 - 30 %) and 46 % (CI95 % = 41 - 51 %) lower apparent clearance, respectively, compared to normal and ultrarapid metabolisers (NM+UM). Early relapse (19 patients) was not associated with model-estimated, concentration-based or declared adherence in the total population (p = 0.41, p = 0.37 and p = 0.45, respectively). CONCLUSIONS: These findings will help future investigations focusing on the exposure-efficacy relationship for letrozole in adjuvant setting.

Asunto(s)

Inhibidores de la Aromatasa , Neoplasias de la Mama , Letrozol , Cumplimiento de la Medicación , Humanos , Letrozol/farmacocinética , Letrozol/administración & dosificación , Letrozol/uso terapéutico , Letrozol/sangre , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Persona de Mediana Edad , Anciano , Inhibidores de la Aromatasa/farmacocinética , Inhibidores de la Aromatasa/administración & dosificación , Inhibidores de la Aromatasa/uso terapéutico , Inhibidores de la Aromatasa/sangre , Adulto , Quimioterapia Adyuvante/métodos , Modelos Biológicos , Estudios Prospectivos , Receptores de Estrógenos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Antineoplásicos/sangre , Antineoplásicos/administración & dosificación , Anciano de 80 o más Años

RESUMEN

Oxaliplatin (L-OHP), a third-generation platinum-based anti-tumor drug, finds widespread application in the first-line treatment of metastatic colorectal cancer. Despite its efficacy, the drug's usage is curtailed by a litany of side effects, with L-OHP-induced peripheral neuropathy (OIPN) being the most debilitating. This condition can be classified into varying degrees of severity. Employing serum metabolomics, a high-sensitivity, high-throughput technique, holds promise as a method to identify biomarkers for clinical assessment and monitoring of OIPN patients across different severity levels. In our study, we analyzed serum metabolites in patients with different OIPN levels using ultra-performance liquid chromatography-high resolution mass spectrometry. By employing statistical analyses and pathway enrichment studies, we aimed to identify potential biomarkers and metabolic pathways. Our findings characterized the serum metabolic profiles of patients with varying OIPN levels. Notably, pathway analysis revealed a significant correlation with lipid metabolism, amino acid metabolism, and energy metabolism. Multivariate statistical analysis and receiver operator characteristic curve evaluation pointed to anhalamine and glycochenodeoxycholic acid as potential biomarkers for OIPN C and A, which suggest that serum metabolomics may serve as a potent tool for exploring the metabolic status of patients suffering from diverse diseases and for discovering novel biomarkers.

Asunto(s)

Metabolómica , Oxaliplatino , Humanos , Masculino , Femenino , Persona de Mediana Edad , Antineoplásicos/sangre , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/sangre , Enfermedades del Sistema Nervioso Periférico/metabolismo , Cromatografía Líquida de Alta Presión , Anciano , Biomarcadores/sangre , Síndromes de Neurotoxicidad/sangre , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/diagnóstico