RESUMO
The aim of the present study was to determine whether the trough plasma concentrations (C0) of regorafenib and its metabolites, the N-oxide metabolite (M-2) and the desmethyl N-oxide metabolite (M-5), in 21 patients receiving regorafenib therapy were affected by albumin-bilirubin (ALBI) grade. Regorafenib was administered at dosages ranging from 40 to 160 mg once daily on a 3-week-on, 1-week-off cycle. C0 values of regorafenib and its major metabolites were measured by high-performance liquid chromatography on day 8 after treatment initiation. The C0 values of regorafenib and metabolites M-2 and M-5 were significantly lower in patients with ALBI grade 2 as compared with grade 1 (P = 0.023, 0.003 and 0.017, respectively). The total C0 of regorafenib and its metabolites was significantly higher in ALBI grade 1 patients relative to grade 2 (3.489 µg/mL vs. 1.48 µg/mL; P = 0.009). The median relative dose intensity (RDI) of patients categorized as ALBI grade 2 was significantly lower than that of grade 1 patients (21.9% vs. 62.9%; P = 0.006). In 15 colorectal cancer patients among the total 21 patients, patients with ALBI grade 2 (n = 9) had a significantly shorter median overall survival time than patients with grade 1 (n = 6; P = 0.013). Administering a low dose of regorafenib to patients with ALBI grade 2 reduces the RDI of regorafenib and lowers treatment efficacy, as an appropriate C0 of regorafenib is not maintained. Monitoring the C0 of regorafenib regularly is necessary to guide dose adjustment.
Assuntos
Bilirrubina , Compostos de Fenilureia , Piridinas , Humanos , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/sangue , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Piridinas/farmacocinética , Piridinas/sangue , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Bilirrubina/sangue , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/sangue , Idoso de 80 Anos ou mais , Adulto , Japão , Povo Asiático , Albumina Sérica/metabolismo , População do Leste AsiáticoRESUMO
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.
Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Teste em Amostras de Sangue Seco , Monitoramento de Medicamentos , Receptores ErbB , Neoplasias Pulmonares , Mutação , Inibidores de Proteínas Quinases , Humanos , Compostos de Anilina/sangue , Compostos de Anilina/uso terapêutico , Compostos de Anilina/farmacocinética , Acrilamidas/sangue , Acrilamidas/uso terapêutico , Projetos Piloto , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangue , Monitoramento de Medicamentos/métodos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/sangue , Teste em Amostras de Sangue Seco/métodos , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Cromatografia Líquida/métodos , Idoso de 80 Anos ou mais , Adulto , Indóis , PirimidinasRESUMO
BACKGROUND: Volumetric Absorptive Microsampling (VAMS) is a useful tool for therapeutic drug monitoring (TDM) of oral targeted anticancer agents. VAMS aims to improve safety and efficacy by enabling at-home blood sample collection by patients. This study aimed to develop and validate an ultra-high performance liquid chromatography-tandem mass spectrometry method for the quantitative determination of abiraterone, alectinib, cabozantinib, imatinib, olaparib, sunitinib, and the metabolites, Δ(4)-abiraterone (D4A), alectinib-M4, imatinib-M1, and N -desethyl sunitinib, in dried whole blood samples using VAMS to support TDM. METHODS: After the collection of 10 µL of whole blood sample using the VAMS device, the analytes were extracted from the tip using methanol with shaking, evaporated, and reconstituted in acetonitrile:0.1 mol/L ammonium hydroxide in water (1:1, vol/vol). The extracts were then analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry. Validation experiments based on the ICH M10 guideline were carried out, and stability was evaluated under shipping and storage conditions. VAMS specimens were collected in the outpatient clinic to demonstrate the applicability of the assay. RESULTS: The validated range of the method was considered accurate and precise for all analytes. Accordingly, the validation experiments met the relevant requirements, except for cross-analyte interference. Based on the stability data, shipment can be performed at room temperature within 14 days after sample collection and the VAMS specimen can be stored up to 9 months at -20 and -70°C. Samples from 59 patients were collected at the hospital. CONCLUSIONS: The developed method could be used to successfully quantify the concentrations of abiraterone, D4A, alectinib, alectinib-M4, cabozantinib, imatinib, imatinib-M1, olaparib, sunitinib, and N -desethyl sunitinib within the validated range using VAMS. Therefore, the method can be used to estimate the dried whole blood-to-plasma ratios for TDM in the clinic.
Assuntos
Antineoplásicos , Monitoramento de Medicamentos , Espectrometria de Massas em Tandem , Humanos , Monitoramento de Medicamentos/métodos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Administração Oral , Teste em Amostras de Sangue Seco/métodos , Mesilato de Imatinib/sangue , Mesilato de Imatinib/farmacocinéticaRESUMO
BACKGROUND: Osimertinib is an oral small-molecule tyrosine kinase receptor inhibitor used to treat non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor mutation. Patients may experience drug toxicity and require dose deescalation. The study aimed to quantitate osimertinib and its 2 active metabolites, AZ5104 and AZ7550, in microsampled dried blood spots (DBS) collected from patients with NSCLC using a hemaPEN device and compare them with plasma drug levels. METHODS: A 6-min ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed and validated using plasma and DBS. The accuracy, selectivity, matrix effect, recovery, and stability were assessed using bioanalytical validation criteria. The hematocrit effect was investigated in DBS. Drug levels were measured in 15 patients with NSCLC, and the Bland-Altman method was used to compare measurements between plasma and DBS. RESULTS: The validated assay determined accurate and precise quantities, respectively, for osimertinib in both plasma (93.2%-99.3%; 0.2%-2.3%) and DBS (96.7%-99.6%; 0.5%-10.3%) over a concentration of 1-729 ng/mL. The osimertinib metabolites, AZ5104 and AZ7550, were similarly validated in accordance with bioanalytical guidelines. For 30%-60% patient hematocrit, no hematocrit bias was observed with DBS for all analytes. The Bland-Altman method showed high concordance between plasma and DBS analyte levels. Stability experiments revealed that osimertinib and its metabolites were poorly stable in plasma at room temperature, whereas all analytes were stable in DBS for 10 days at room temperature. CONCLUSIONS: The measurement of osimertinib, AZ5104, and AZ7550 from hemaPEN microsampled DBS is a convenient and reliable approach for therapeutic drug monitoring that produces measurements consistent with plasma drug levels.
Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Teste em Amostras de Sangue Seco , Neoplasias Pulmonares , Espectrometria de Massas em Tandem , Humanos , Compostos de Anilina/sangue , Teste em Amostras de Sangue Seco/métodos , Acrilamidas/sangue , Espectrometria de Massas em Tandem/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/sangue , Cromatografia Líquida de Alta Pressão/métodos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/sangue , Monitoramento de Medicamentos/métodos , Reprodutibilidade dos Testes , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Indóis , PirimidinasRESUMO
BACKGROUND: Imatinib treatment for certain cancers can lead to elevated creatine kinase (CK) levels, potentially indicating muscle injury, and ongoing research aims to understand the correlation between imatinib levels and creatine kinase to assess its impact on treatment response. METHODS: This single-center observational study involved 76 chronic myeloid leukemia (CML) patients receiving imatinib treatment, focusing on evaluating drug and metabolite levels using liquid chromatography-mass spectrometry (LC-MS-MS) instrumentation. Serum CK and creatine kinase-MB (CK-MB) levels were assessed using Colorimetric kits. RESULTS: CK and CK-MB levels were measured, CK showed a median value of 211.5 IU/l and CK-MB showed a median value of 4.4 IU/l. Comparing low and high CK groups, significant differences were found in peak and trough plasma concentrations of imatinib and its metabolites. Correlations between CK levels and pharmacokinetic parameters were explored, with notable associations identified. Binary logistic regression revealed predictors influencing the therapeutic response to imatinib and categorized expected CK levels into high or low, with peak levels of imatinib emerging as a significant predictor for CK level categorization. CONCLUSION: The study highlights the link between imatinib's pharmacokinetics and elevated CK levels, indicating a possible correlation between specific metabolites and improved treatment response. Individualized monitoring of CK levels and imatinib pharmacokinetics could enhance care for CML patients.
Assuntos
Antineoplásicos , Creatina Quinase , Monitoramento de Medicamentos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/farmacocinética , Mesilato de Imatinib/uso terapêutico , Mesilato de Imatinib/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/sangue , Creatina Quinase/sangue , Idoso , Monitoramento de Medicamentos/métodos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/sangue , Adulto Jovem , Resultado do Tratamento , Creatina Quinase Forma MB/sangue , Espectrometria de Massas em Tandem , Idoso de 80 Anos ou mais , Cromatografia LíquidaRESUMO
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.
Assuntos
Metabolômica , Oxaliplatina , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Antineoplásicos/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/metabolismo , Cromatografia Líquida de Alta Pressão , Idoso , Biomarcadores/sangue , Síndromes Neurotóxicas/sangue , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/diagnósticoRESUMO
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.
Assuntos
Antineoplásicos , Técnicas Biossensoriais , Bleomicina , Cisplatino , Eletrodos , Bleomicina/sangue , Cisplatino/sangue , Humanos , Técnicas Biossensoriais/métodos , Antineoplásicos/sangue , Antineoplásicos/análise , Albumina Sérica Humana/análise , Técnicas Eletroquímicas/métodos , Ouro/químicaRESUMO
BACKGROUND: Imatinib mesylate (IM) is the standard chemotherapy for patients with gastrointestinal stromal tumors (GISTs) and has a favorable safety profile. Pharmacokinetics (PK), such as plasma trough concentration (Cmin), varies among patients, requiring the need for therapeutic drug monitoring (TDM) during IM administration. Despite some reports from overseas, the relationship between Cmin, adverse events (AEs), and treatment efficacy in Japanese patients with GIST has still been lacking. This study aimed to investigate the relationship between IM plasma concentration and AEs in Japanese patients with GISTs. METHODS: This retrospective study analyzed the data of 83 patients who underwent IM treatment for GISTs at our institution between May 2002 and September 2021. RESULTS: The IM Cmin was associated with any grade of AEs (with AEs vs. without AEs = 1294 (260-4075) vs. 857 (163-1886) ng/mL, P < 0.001), edema (with edema vs. without edema = 1278 (634-4075) vs. 1036 (163-4069) ng/mL, P = 0.017), and fatigue (with fatigue vs. without fatigue = 1373 (634-4069) vs. 1046 (163-4075) ng/mL, P = 0.044). Moreover, a Cmin ≥ 1283 ng/mL was a risk factor for severe AEs. The median progression-free survival (PFS) was 3.04 years in the lowest Cmin tertile (T1, < 917 ng/mL) compared with 5.90 years for T2 and T3 (P = 0.010). CONCLUSION: Edema and fatigue are potentially associated with IM plasma trough concentrations of ≥ 1283 ng/mL in Japanese patients with GISTs. Further, maintaining an IM plasma trough concentration above 917 ng/mL may improve PFS.
Assuntos
Antineoplásicos , Monitoramento de Medicamentos , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Humanos , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , População do Leste Asiático , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/sangue , Mesilato de Imatinib/uso terapêutico , Estudos Retrospectivos , Monitoramento de Medicamentos/métodos , Resultado do Tratamento , Edema/induzido quimicamente , Edema/etiologia , Fadiga/induzido quimicamente , Fadiga/etiologiaRESUMO
Nanoparticle-based drug targeting is an important platform for the treatment of cardiovascular disorders. Magnetic drug targeting is more significant as it is a noninvasive procedure and biocompatible. The present problem aims to understand magnetic drug delivery to a specific location in a permeable blood vessel under the vibration and magnetic environment. Caputo-Fabrizio fractional-order time derivatives are used in the governing equations. The momentum equations are solved analytically and presented in the form of Lorenzo-Hartley and Robotonov-Hartley functions and convolution of the Laplace transform. Convolution integrations are solved by using the numerical integration technique. The Fourth order Runge-Kutta method (RK4) is used to solve the force balance equation. The influence of pertinent parameters such as Reynolds number, pulsatile frequency, magnetic field strength, Darcy number and fractional-order parameters are presented through graphs. It is observed that increasing Reynolds number results in decreasing the tendency of the drug to capture near the tumor site, whereas the pulsatile frequency presents an opposite phenomenon. Increasing the magnetic field strength and Darcy number boosts the capture efficiency of drug particles near the tumor site. The short memory effect efficiently captures the magnetic drug carriers to a specific location under the action of suitable magnetic field strength.
Assuntos
Antineoplásicos/sangue , Vasos Sanguíneos/metabolismo , Portadores de Fármacos , Campos Magnéticos , Nanopartículas Metálicas , Modelos Cardiovasculares , Neoplasias/irrigação sanguínea , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Simulação por Computador , Composição de Medicamentos , Nanotecnologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Análise Numérica Assistida por Computador , Permeabilidade , Fluxo Sanguíneo RegionalRESUMO
Asparaginase is commonly used in combination therapy of acute lymphoblastic leukemia. However, as an immunogenic protein, hypersensitivity reactions (HSRs) during asparaginase therapy are frequent, indicating the development of anti-asparaginase antibodies. These can be associated with diminished clinical effectiveness, including poorer survival. Therapeutic drug monitoring of serum asparaginase activity to confirm complete asparagine depletion is therefore crucial during asparaginase therapy. Switching to alternative types of asparaginase is recommended for patients experiencing HSRs or silent inactivation; those with HSRs or silent inactivation on Escherichia coli-derived asparaginases should switch to another preparation. However, prior global shortages of Erwinia asparaginase highlight the importance of alternative non-E. coli-derived asparaginase, including recombinant Erwinia asparaginase.
Asparaginase is commonly used as a part of a multidrug regimen for acute lymphoblastic leukemia treatment. As foreign proteins, asparaginases have the potential to induce immune responses known as hypersensitivity reactions (HSRs), which can range from a mild rash to a severe allergic reaction. Here, we provide an overview of HSRs and their prevalence in asparaginase-based therapies, and clinical approaches to reduce HSRs. We also review the current understanding of cellular and molecular mechanisms of HSRs, consequences of HSRs and current recommendations for the management of immune reactions to asparaginase. Prior global shortages of Erwinia asparaginase due to manufacturing and supply issues have limited access of asparaginase treatment to patients. In this context, newer therapies have recently been developed.
Assuntos
Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antineoplásicos/sangue , Antineoplásicos/imunologia , Asparaginase/sangue , Asparaginase/imunologia , Linfócitos B/imunologia , Criança , Hipersensibilidade a Drogas/imunologia , Monitoramento de Medicamentos , Feminino , Humanos , Imunoglobulina M/sangue , Masculino , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
Furmonertinib was designed for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation. In this study, we investigated the metabolic disposition and mass balance in humans and tissue distribution in rats. After a single oral administration of 97.9 µCi/81.5 mg [14C]-furmonertinib mesylate to six healthy male volunteers, the absorption process of furmonertinib was fast with a tmax of total plasma radioactivity at 0.75 h. Afterward, furmonertinib was extensively metabolized, with the parent drug and active metabolite AST5902 accounting for 1.68% and 0.97% of total radioactivity in plasma. The terminal t1/2 of total radioactivity in plasma was as long as 333 h, suggesting that the covalent binding of drug-related substances to plasma proteins was irreversible to a great extent. The most abundant metabolites identified in feces were desmethyl metabolite (AST5902), cysteine conjugate (M19), and parent drug (M0), which accounted for 6.28%, 5.52%, and 1.38% of the dose, respectively. After intragastric administration of 124 µCi/9.93 mg/kg [14C]-furmonertinib to rats, drug-related substances were widely and rapidly distributed in tissues within 4 h. The concentration of total radioactivity in the lung was 100-fold higher than that in rat plasma, which could be beneficial to the treatment of lung cancer. Mass balance in humans was achieved with 77.8% of the administered dose recovered in excretions within 35 days after administration, including 6.63% and 71.2% in urine and feces, respectively. In conclusion, [14C]-furmonertinib is completely absorbed and rapidly distributed into lung tissue, extensively metabolized in humans, presented mostly as covalent conjugates in plasma, and slowly eliminated mostly via fecal route.
Assuntos
Antineoplásicos , Adulto , Animais , Feminino , Humanos , Masculino , Ratos , Administração Oral , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Cromatografia Líquida de Alta Pressão , Receptores ErbB/antagonistas & inibidores , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
WHAT IS KNOWN AND OBJECTIVE: Sunitinib is used as a first-line therapy for metastatic renal cell carcinoma. The primary aim of this study was to determine the optimal total sunitinib (sunitinib plus N-desethyl sunitinib) trough concentration for the alternative dosing schedule: 2-week-on and 1-week-off schedule (2/1 schedule). METHODS: Patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib, whose total sunitinib concentrations were available, were recruited for this study. Out of 19 patients, 17 whose sunitinib dosage was not changed until the measurement of drug concentration were eligible for the analysis of the relationship between total sunitinib concentration and clinical outcome. Individual pharmacokinetic parameters in 19 patients were estimated via the Bayesian analysis. RESULTS: The onset of severe (grade ≥3) adverse effects among 17 patients during 3 weeks as a first course of sunitinib therapy was observed in 7 (41.2%) patients. The median total sunitinib concentration in patients with severe adverse effects was significantly higher compared with that in patients without severe adverse effects [median: 119 (113-131) vs. 87.8 (77.4-102) ng/mL, p = 0.01]. According to the receiver operating characteristic analysis of the onset of severe adverse effects, the cut-off value of the total sunitinib concentration was 108 ng/mL. Patients with a total sunitinib concentration lower than 108 ng/mL had a longer time to first dose reduction or withdrawal due to adverse effects compared with those with a total sunitinib concentration of 108 ng/mL or higher (p = 0.03). The probability without treatment failure was not significantly different between the two concentration groups. In addition, the estimated sunitinib apparent oral clearance (CL/F) was significantly lower in the severe adverse effects group. Our simulation demonstrated that 0.67-time dose is needed for patients with approximately 90.0 ng/mL of sunitinib concentration on day 7 to maintain the concentration at the same level as the patients with higher CL/F. WHAT IS NEW AND CONCLUSION: Maintaining the total sunitinib trough concentrations of less than 108 ng/mL is safe to avoid the onset of serious adverse effects without increasing the treatment failure in patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib.
Assuntos
Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Sunitinibe/sangue , Sunitinibe/uso terapêutico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/patologia , Esquema de Medicação , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Gravidade do Paciente , Estudos Retrospectivos , Sunitinibe/administração & dosagem , Sunitinibe/efeitos adversosRESUMO
The treatment of cancer is one of the most important pharmacotherapeutic challenges. To this end, chemotherapy has for some time been complemented by targeted therapies against specific structures. PDA-66, a structural analogue of the inhibitor of serine-threonine kinase glycogen synthase kinase 3ß SB216763, has shown preclinical antitumour effects in various cell lines, with the key pathways of its anticancer activity being cell cycle modulation, DNA replication and p53 signalling. For the monitoring of anticancer drug treatment in the context of therapeutic drug monitoring, the determination of plasma concentrations is essential, for which an LC-MS/MS method is particularly suitable. In the present study, a sensitive LC-MS/MS method for the quantification of the potential anticancer drug PDA-66 in human plasma with a lower limit of quantification of 2.5 nM is presented. The method was successfully validated and tested for the determination of PDA-66 in mouse plasma and sera.
Assuntos
Antineoplásicos/sangue , Cromatografia Líquida/métodos , Indóis/sangue , Maleimidas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Humanos , Limite de Detecção , Camundongos , Reprodutibilidade dos TestesRESUMO
Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM. Part 1 of the study, reported here, evaluated a mix-and-deliver (MD) formulation of daratumumab and rHuPH20 (DARA-MD) administered by subcutaneous infusion. Patients received subcutaneous daratumumab according to the approved IV monotherapy dosing schedule at 1200 mg (n = 8) or 1800 mg (n = 45). Primary end points were safety and pharmacokinetic (PK) variables. The most common treatment-emergent adverse events with DARA-MD 1200 mg were thrombocytopenia, upper respiratory tract infection, insomnia, and decreased appetite (37.5% each). Anemia (33.3%), upper respiratory tract infection, pyrexia, and diarrhea (26.7% each) were the most common treatment-emergent adverse events with DARA-MD 1800 mg. One patient in the 1200-mg dose group (12.5%) and 11 patients in the 1800-mg dose group (24.4%) experienced infusion-related reactions, which were generally grade 1/2 and typically occurred at the first infusion. The 1800 mg dose achieved similar or greater serum concentrations compared with the 16 mg/kg IV dose. Overall response rates of 25.0% and 42.2% were achieved with 1200-mg and 1800-mg DARA-MD, respectively. Subcutaneous administration of DARA-MD was well tolerated in patients with relapsed or refractory MM, with the 1800-mg dose exhibiting PK concentrations and responses consistent with IV daratumumab in a similar patient population. This study was registered at www.clinicaltrials.gov as #NCT02519452.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do TratamentoRESUMO
PENAO (4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid) is a second-generation peptide arsenical that inactivates mitochondria in proliferating tumour cells by covalently reacting with mitochondrial inner-membrane adenine nucleotide transferase. The toxicokinetics of PENAO has been investigated in Sprague-Dawley rats to inform route of administration and dosing for human clinical trials. PENAO was well tolerated at 3.3 mg/kg daily intravenous injections but associated with significant toxicity at 10 mg/kg, primarily in the males. The major target organ for toxic effects was the kidney, with changes observed in tubular dilation, presence of casts, basophilic tubules, lymphoid aggregates and interstitial fibrosis. Kidney function was impaired in males with dose-dependent increase in serum creatinine concentration. The severity of the microscopic lesions was reduced in the females, but not the males, at the completion of the four-week recovery period. The elimination phase half-life of PENAO varied between 0.4 and 1.7 h and volume of distribution ranged from 0.25 to 0.88 L/kg for the different dose groups and treatment days, suggesting that PENAO distributes in the extracellular fluids at the doses tested. The area under the curve and clearance values indicate that male rats had reduced elimination of PENAO compared to females, which may account for the increased toxicity in males. PENAO is significantly better tolerated in rodents than its predecessor, GSAO. As GSAO was generally well tolerated with few side effects in a phase I trial in patients with solid tumours, these findings bode well for the tolerability of intravenous dosing of PENAO in patients.
Assuntos
Antineoplásicos , Arsenicais , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Área Sob a Curva , Arsenicais/efeitos adversos , Arsenicais/sangue , Arsenicais/farmacocinética , Creatinina/sangue , Feminino , Meia-Vida , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Taxa de Depuração Metabólica , Mitocôndrias , Ratos Sprague-Dawley , ToxicocinéticaRESUMO
BACKGROUND: Entrectinib is an oral, CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, tyrosine kinase ROS proto-oncogene 1, and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe 3 clinical studies, including one investigating the single/multiple dose pharmacokinetics of entrectinib in patients and two studies in healthy volunteers investigating the absorption/distribution/metabolism/excretion (ADME) of entrectinib, its relative bioavailability, and effect of food on pharmacokinetics. METHODS: The patient study is open-label with dose-escalation and expansion phases. Volunteers received entrectinib (100-400 mg/m2, and 600-800 mg) once daily with food in continuous 28-day cycles. In the ADME study, volunteers received a single oral dose of [14C]entrectinib 600 mg. In the third study, volunteers received single doses of entrectinib 600 mg as the research and marketed formulations in the fasted state (Part 1), and the marketed formulation in the fed and fasted states (Part 2). Entrectinib and its major active metabolite M5 were assessed in all studies. RESULTS: Entrectinib was absorbed in a dose-dependent manner with maximum concentrations at ~4 h postdose and an elimination half-life of ~20 h. Entrectinib was cleared mainly through metabolism and both entrectinib and metabolites were eliminated mainly in feces (minimal renal excretion). At steady-state, the M5-to-entrectinib AUC ratio was 0.5 (with 600 mg entrectinib research formulation in patients). The research and marketed formulations were bioequivalent and food had no relevant effect on pharmacokinetics. CONCLUSIONS: Entrectinib is well absorbed, with linear PK that is suitable for once-daily dosing, and can be taken with or without food.
Assuntos
Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Indazóis/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/urina , Benzamidas/administração & dosagem , Benzamidas/sangue , Benzamidas/urina , Cápsulas , Estudos Cross-Over , Jejum/metabolismo , Fezes/química , Feminino , Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Indazóis/administração & dosagem , Indazóis/sangue , Indazóis/urina , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/urina , Equivalência Terapêutica , Adulto JovemRESUMO
The conventional techniques in treating cancerous cells in a human body are conducted either by surgery or oral medication or injecting anticancer drugs, which may have several side effects on healthy cells. Compared to these techniques, site-specific delivery of drugs can be one of the pillars of cancer treatment. It could allow for better treatment efficiency and lesser adverse effects. A promising drug delivery approach is magnetic drug targeting, which can be realized if a drug delivery vehicle possesses an intense magnetic moment. Here, we discuss different types of magnetic nanomaterials, which can be used as magnetic drug delivery vehicles, approaches to magnetically targeted delivery, and promising strategies for the enhancement of the imaging-guided delivery and the therapeutic action. The present study aims to discuss all significant factors that influence the process of magnetic drug targeting through microvessels, such as fluidic force, magnetic force, particle-particle interaction, inertia force, Saffman lift force, and permeability of the microvessel. We consider the nature of blood flow as non-Newtonian in single-phase and two-phase models so that a realistic rheological model for an effective magnetic drug targeting can be established through proper comparison. Here we present a comprehensive mathematical model on magnetic drug targeting that could help the medical experts and biomedical engineers in applying the methodology of magnetic drug targeting effectively to cure cancerous disease.
Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos , Sistemas de Liberação de Medicamentos/instrumentação , Imãs , Microvasos/fisiologia , Modelos Cardiovasculares , Nanopartículas , Neoplasias/irrigação sanguínea , Animais , Antineoplásicos/sangue , Antineoplásicos/química , Velocidade do Fluxo Sanguíneo , Humanos , Hidrodinâmica , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Permeabilidade , Fluxo Sanguíneo RegionalRESUMO
Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. We report on a 63-year-old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic overdose symptoms such as nausea and vomiting grade 1 and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased (grade 1) and QTc slightly prolonged. The plasma concentration 3 h after the last dose was 2110 ng/mL. We describe the course of a case with a chronic overdose during 16 days of the double dose of encorafenib as well as the followed approach, which could be taken into account when observing an encorafenib overdose. Providing information in times of Covid-19 is challenging, but remains necessary for good clinical care.
Assuntos
Carbamatos , Overdose de Drogas , Testes de Função Hepática/métodos , Síndrome do QT Longo , Conduta do Tratamento Medicamentoso/normas , Melanoma , Neoplasias Cutâneas , Sulfonamidas , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , COVID-19/epidemiologia , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Carbamatos/sangue , Controle de Doenças Transmissíveis , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Overdose de Drogas/sangue , Overdose de Drogas/diagnóstico , Overdose de Drogas/etiologia , Overdose de Drogas/fisiopatologia , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Masculino , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/sangue , Vômito/induzido quimicamente , Vômito/diagnósticoRESUMO
BACKGROUND AND PURPOSE: Pralsetinib is an FDA-approved oral small-molecule inhibitor for treatment of rearranged during transfection (RET) proto-oncogene fusion-positive non-small cell lung cancer. We investigated how the efflux transporters ABCB1 and ABCG2, the SLCO1A/1B uptake transporters and the drug-metabolizing enzyme CYP3A influence pralsetinib pharmacokinetics. EXPERIMENTAL APPROACH: In vitro, transepithelial pralsetinib transport was assessed. In vivo, pralsetinib (10 mg/kg) was administered orally to relevant genetically modified mouse models. Pralsetinib concentrations in cell medium, plasma samples and organ homogenates were measured using liquid chromatography-tandem mass spectrometry. KEY RESULTS: Pralsetinib was efficiently transported by human (h)ABCB1 and mouse (m)Abcg2, but not hACBG2. In vivo, mAbcb1a/1b markedly and mAbcg2 slightly limited pralsetinib brain penetration (6.3-and 1.8-fold, respectively). Testis distribution showed similar results. Abcb1a/1b;Abcg2-/- mice showed 1.5-fold higher plasma exposure, 23-fold increased brain penetration, and 4-fold reduced recovery of pralsetinib in the small intestinal content. mSlco1a/1b deficiency did not affect pralsetinib oral availability or tissue exposure. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted pralsetinib plasma exposure (1.3-fold) and brain penetration (19.6-fold) in wild-type mice. Additionally, pralsetinib was a modest substrate of mCYP3A, but not of hCYP3A4, which did not noticeably restrict the oral availability or tissue distribution of pralsetinib. CONCLUSIONS AND IMPLICATIONS: SLCO1A/1B and CYP3A4 are unlikely to affect the pharmacokinetics of pralsetinib, but ABCG2 and especially ABCB1 markedly limit its brain and testis penetration, as well as oral availability. These effects are mostly reversed by oral coadministration of the ABCB1/ABCG2 inhibitor elacridar. These insights may be useful in the further clinical development of pralsetinib.
Assuntos
Antineoplásicos/farmacocinética , Transportadores de Ânions Orgânicos/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Pirazóis/farmacocinética , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Administração Oral , Animais , Antineoplásicos/sangue , Disponibilidade Biológica , Encéfalo/metabolismo , Citocromo P-450 CYP3A/genética , Feminino , Masculino , Camundongos Knockout , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/genética , Inibidores de Proteínas Quinases/sangue , Pirazóis/sangue , Piridinas/sangue , Pirimidinas/sangue , Testículo/metabolismoRESUMO
Hepatocellular carcinoma (HCC) is one of the major cancers with high mortality rate. Traditional drugs used in clinic are usually limited by the drug resistance and side effect and novel agents are still needed. Macrolide brefeldin A (BFA) is a well-known lead compound in cancer chemotherapy, however, with poor solubility and instability. In this study, to overcome these disadvantages, BFA was encapsulated in mixed nanomicelles based on TPGS and F127 copolymers (M-BFA). M-BFA was conferred high solubility, colloidal stability, and capability of sustained release of intact BFA. In vitro, M-BFA markedly inhibited the proliferation, induced G0/G1 phase arrest, and caspase-dependent apoptosis in human liver carcinoma HepG2 cells. Moreover, M-BFA also induced autophagic cell death via Akt/mTOR and ERK pathways. In HepG2 tumor-bearing xenograft mice, indocyanine green (ICG) as a fluorescent probe loaded in M-BFA distributed to the tumor tissue rapidly, prolonged the blood circulation, and improved the tumor accumulation capacity. More importantly, M-BFA (10 mg/kg) dramatically delayed the tumor progression and induced extensive necrosis of the tumor tissues. Taken together, the present work suggests that M-BFA has promising potential in HCC therapy.