RESUMO
Genetic variations in CYP3A4, CYP3A5, and m-TOR could contribute to interpatient variability regarding m-TOR inhibitors pharmacokinetics or cellular effects. The purpose of this study was to evaluate the influence of selected candidate variations in these genes on everolimus pharmacokinetics, efficacy, and toxicity in cancer patients. Thirty-four patients receiving everolimus for breast (n = 22) or renal (n = 10) cancers, or neuroendocrine tumors of pancreatic origin (n = 2) were included in the study. Six variants in genes related to everolimus pharmacokinetics (CYP3A4*22 and CYP3A5*3) or pharmacodynamics (m-TOR rs2295079, rs2295080, rs2024627 and rs1057079) were genotyped. Associations with trough concentrations (C0), dose reductions, or treatment interruptions due to toxicity and progression-free survival were investigated using generalized estimating equations and Cox models. CYP3A5 nonexpressers had significantly higher C0 as compared with expressers (ßGG vs AG = + 6.32 ± 2.22 ng/mL, p = 0.004). m-TOR rs2024627 was significantly associated with an increased risk of cancer progression studied alone or as part of an haplotype (T vs C: HR = 2.60, 95% CI [1.16-5.80], p = 0.020; CTCG vs other haplotypes HR = 2.29, 95% CI [1.06-4.95], p = 0.035, respectively). This study showed that CYP3A5 expression impacts everolimus pharmacokinetics in cancer patients and identified a genetic variation in m-TOR associated with the risk of cancer progression.
Assuntos
Antineoplásicos/sangue , Citocromo P-450 CYP3A/genética , Everolimo/sangue , Neoplasias/tratamento farmacológico , Neoplasias/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Serina-Treonina Quinases TOR/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Progressão da Doença , Monitoramento de Medicamentos , Everolimo/efeitos adversos , Everolimo/farmacocinética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/mortalidade , Farmacogenética , Fenótipo , Intervalo Livre de Progressão , Estudos Retrospectivos , Serina-Treonina Quinases TOR/metabolismoRESUMO
Trastuzumab is a monoclonal antibody used to treat human epidermal growth receptor 2 positive (HER2+) breast cancers either by itself or in combination with other chemotherapy medication. Marketing authorization was granted for a subcutaneous form of the antibody in 2014. In this case report, we discuss our experience with a patient who took part in a therapeutic education program on self-administration of trastuzumab. We demonstrate that these types of self-administered injections are not only possible but also are toxicity-free. Based on the tolerance data and our patient's experience, we propose that the current regulations be relaxed regarding the availability of trastuzumab subcutaneous form in order to develop a cheaper "city scheme," i.e. self-administered injections.
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Educação de Pacientes como Assunto/métodos , Trastuzumab/administração & dosagem , Adulto , Neoplasias da Mama/genética , Feminino , Humanos , Injeções Subcutâneas , Receptor ErbB-2/genética , AutoadministraçãoRESUMO
INTRODUCTION: Therapeutic drug monitoring (TDM) of everolimus is not performed in oncology and no trough level (C0) target has been yet defined. The aim of this study was to determine everolimus C0 target for toxicity and efficacy. MATERIALS AND METHODS: Clinical, biological and radiologic data from 54 patients were collected. Toxicity event was defined by termination, temporary interruption and/or dose reduction of everolimus while efficacy was defined as progression-free survival. C0 values were dichotomized by ROC curve analysis and the association between exposure and outcome was determined using Cox models for repeated events (toxicity) or Cox model censured at the first event (progression free survival). RESULTS: Among the 42 patients (77.8%) with breast cancer, 10 (18.5%) kidney cancer and 2 (3.7%) neuroendocrine cancer, adverse events were reported in 75.9% of the patients (everolimus termination in 25.9% patients). C0 everolimus higher than 26.3ng/mL (Sen=0.38,Spe=0.88) were associated with a 4-fold increased risk of toxicity (HR=4.12, IC95%=[1.48-11.5], p=0.0067) whereas C0 lower than 11.9ng/mL were associated with a 3-fold increased risk of progression (HR=3.2, IC95%=[1.33-7.81],p=0.001). DISCUSSION: Further studies are required to evaluate the everolimus C0 threshold proposed for toxicity (26.3ng/mL) and for progression (11.9ng/mL) especially with a large number of patients and more homogeneous types of cancer. However, these results are in favour of TDM for everolimus in oncology.
Assuntos
Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Monitoramento de Medicamentos , Everolimo/sangue , Everolimo/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Progressão da Doença , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Everolimo/efeitos adversos , Everolimo/farmacologia , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias/patologiaRESUMO
PURPOSE: This study aims to investigate the impact of medication reconciliation (MR) conducted by pharmacists before patient enrollment and the initiation of investigational treatments. By implementing MR, the primary objective is to evaluate the extent to which the inclusion of patients with prohibited or not recommended concomitant medications in clinical trials can be significantly reduced. MATERIALS AND METHODS: The study included all patients who participated in clinical trials and underwent MR between September 1, 2015, and September 1, 2020. To identify prohibited or monitored drugs, protocols and investigator's brochures provided by the sponsor were meticulously reviewed and taken into consideration. RESULTS: MR was performed for 501 patients, uncovering 35% of the medications they were currently taking. Through the pharmaceutical analysis, a total of 346 drug-drug interactions (DDIs) were identified, of which 188 required monitoring and 158 were strictly prohibited. More than half of the prohibited medications were herbal drugs. A significant portion of these prohibited drugs were discontinued, with only 6% being replaced by suitable alternatives. The implementation of MR played a crucial role in the identification of 51% of the prohibited or monitored drugs that were initially overlooked by oncologists. CONCLUSION: MR is a highly effective measure aimed at reducing the risk of DDIs with investigational drugs, thereby minimizing protocol deviations and enhancing patient care. Sponsors of clinical trials value its implementation and recognize the substantial benefits it brings to the entire trial process. Consequently, many sponsors willingly provide funding to investigational sites that adopt MR as part of their standard practice, acknowledging its critical role in ensuring patient safety and maintaining data integrity throughout the course of clinical research studies.