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
In clinical practice, the determination of unbound drug concentration is very important for dose adjustment and toxicity prediction because only the unbound fraction can achieve a pharmacological effect. A fast, sensitive and accurate analytical method of centrifugal ultrafiltration coupled with high performance liquid chromatography-tandem mass spectrometry method was developed and applied to allow the quantification of unbound lenvatinib concentration. The application of linear regression analysis was used to examine the effects of centrifugal force, centrifugal time, and protein content on ultrafiltrate volume (Vu). The results indicated that the centrifugal force and centrifugal time have an influence on Vu that is significantly positive (P < 0.05). This developed method with good linearity (r2 = 0.9996), good accuracy (bias % ≤ 2.24 %), good precision (CV % ≤ 7.10 %), and good recovery (95.46 %-106.46 %) was suitable for routine clinical practice and studies. Particularly, the ultrafiltration membrane had no non-specific binding to lenvatinib. The unbound fractions can be separated in just 15 min. This method was applied to quantify clinical samples and to determine the plasma protein binding and unbound fraction of lenvatinib. This study provides a more effective and promising method for determination of unbound lenvatinib. It could be beneficial to measure the unbound concentration of lenvatinib in personalized medicine and therapeutic drug monitoring in routine clinical practice.
Assuntos
Compostos de Fenilureia , Quinolinas , Espectrometria de Massas em Tandem , Ultrafiltração , Humanos , Compostos de Fenilureia/sangue , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/química , Compostos de Fenilureia/análise , Quinolinas/sangue , Quinolinas/química , Quinolinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Ultrafiltração/métodos , Modelos Lineares , Reprodutibilidade dos Testes , Ligação Proteica , Limite de DetecçãoRESUMO
Quizartinib is a potent, oral, second-generation, selective type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM-First) study in patients with FLT3-internal tandem duplication (ITD)-positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose-escalation method in each study, including 3 patients who were FLT3-ITD positive. No dose-limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib-related, treatment-emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM-First study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzotiazóis , Quimioterapia de Consolidação , Leucemia Mieloide Aguda , Compostos de Fenilureia , Tirosina Quinase 3 Semelhante a fms , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Feminino , China , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacocinética , Benzotiazóis/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Adulto , Japão , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Quimioterapia de Consolidação/efeitos adversos , Quimioterapia de Consolidação/métodos , Idoso , Quimioterapia de Indução/métodos , Relação Dose-Resposta a DrogaRESUMO
Lenvatinib (LVN) is a potentially effective multiple-targeted receptor tyrosine kinase inhibitor approved for treating hepatocellular carcinoma, metastatic renal cell carcinoma and thyroid cancer. Nonetheless, poor pharmacokinetic properties including poor water solubility and rapid metabolic, complex tumor microenvironment, and drug resistance have impeded its satisfactory therapeutic efficacy. This article comprehensively reviews the uses of nanotechnology in LVN to improve antitumor effects. With the characteristic of high modifiability and loading capacity of the nano-drug delivery system, an active targeting approach, controllable drug release, and biomimetic strategies have been devised to deliver LVN to target tumors in sequence, compensating for the lack of passive targeting. The existing applications and advances of LVN in improving therapeutic efficacy include improving longer-term efficiency, achieving higher efficiency, combination therapy, tracking and diagnosing application and reducing toxicity. Therefore, using multiple strategies combined with photothermal, photodynamic, and immunoregulatory therapies potentially overcomes multi-drug resistance, regulates unfavorable tumor microenvironment, and yields higher synergistic antitumor effects. In brief, the nano-LVN delivery system has brought light to the war against cancer while at the same time improving the antitumor effect. More intelligent and multifunctional nanoparticles should be investigated and further converted into clinical applications in the future.
Assuntos
Antineoplásicos , Sistemas de Liberação de Fármacos por Nanopartículas , Compostos de Fenilureia , Quinolinas , Humanos , Quinolinas/química , Quinolinas/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/farmacologia , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/administração & dosagem , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Sistemas de Liberação de Fármacos por Nanopartículas/química , Animais , Microambiente Tumoral/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Nanopartículas/químicaRESUMO
Aim: Investigation of the pharmacokinetics of sorafenib (SRF) in rats with hepatocellular carcinoma (HCC). Methods: A reproducible ultra-HPLC-MS method for simultaneous determination of serum SRF, N-hydroxymethyl sorafenib and N-demethylation sorafenib. Results: Both the maximum serum concentrations (2.5-times) and the area under the serum concentration-time curve from 0 h to infinity (4.5-times) of SRF were observed to be significantly higher, with a greater than 3.0-fold decrease in the clearance rate in the HCC-bearing rats compared with these values in healthy animals. Further study revealed approximately 3.8- and 3.2-times increases in the apparent Michaelis constant for N-hydroxymethyl sorafenib and N-demethylation sorafenib conversions in the HCC-bearing rats. Conclusion: The low efficiency for the SRF conversions was a key contributor to the increased serum concentrations of SRF.
[Box: see text].
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Niacinamida , Compostos de Fenilureia , Sorafenibe , Sorafenibe/farmacocinética , Sorafenibe/sangue , Sorafenibe/uso terapêutico , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Niacinamida/análogos & derivados , Niacinamida/sangue , Niacinamida/farmacocinética , Ratos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/sangue , Compostos de Fenilureia/uso terapêutico , Cromatografia Líquida de Alta Pressão/métodos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/sangue , Ratos Sprague-Dawley , Espectrometria de MassasRESUMO
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptor-α (PDGFRα), KIT, and RET that have been implicated in pathogenic angiogenesis, tumor growth, and cancer. The primary objective of this work was to evaluate, by establishing quantitative relationships, whether lenvatinib exposure and longitudinal serum biomarker data (VEGF, Ang-2, Tie-2, and FGF-23) are predictors for change in longitudinal tumor size which was assessed based on data from 558 patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving either lenvatinib or placebo treatment. Lenvatinib PK was best described by a 3-compartment model with simultaneous first- and zero-order absorption and linear elimination from the central compartment with significant covariates (body weight, albumin <30 g/dL, ALP>ULN, RR-DTC, RCC, HCC subjects, and concomitant CYP3A inhibitors). Except for body weight, none of the covariates have any clinically meaningful effect on exposure to lenvatinib. Longitudinal biomarker measurements over time were reasonably well defined by a PK/PD model with common EC50, Emax, and a slope for disease progression for all biomarkers. Longitudinal tumor measurements over time were reasonably well defined by a tumor growth inhibition Emax model, which in addition to lenvatinib exposure, included model-predicted relative changes from baseline over time for Tie-2 and Ang-2 as having significant association with tumor response. The developed PK/PD models pave the way for dose optimization and potential prediction of clinical response.
Assuntos
Radioisótopos do Iodo , Compostos de Fenilureia , Quinolinas , Neoplasias da Glândula Tireoide , Humanos , Quinolinas/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Quinolinas/sangue , Quinolinas/farmacologia , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/sangue , Compostos de Fenilureia/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Radioisótopos do Iodo/farmacocinética , Radioisótopos do Iodo/uso terapêutico , Idoso , Biomarcadores Tumorais/sangue , Modelos Biológicos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor TIE-2/sangue , Adulto Jovem , Angiopoietina-2/sangueRESUMO
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.