RESUMO
INTRODUCTION: The therapeutic scenario of metastatic hormone-sensitive prostate cancer (mHSPC) has dramatically changed in recent years, with the approval of new-generation Androgen Receptor Signaling Inhibitors (ARSIs), in combination with the androgen deprivation therapy (ADT), which was the previous standard of care. Despite showing a similar clinical efficacy, ARSIs, all of which are administered orally, are different in terms of pharmacokinetic and drug-drug interactions (DDIs). AREAS COVERED: This review covers the main pharmacokinetic characteristics of ARSIs that have been approved for the first-line therapy of mHSPC patients, underlying the differences among these molecules and focusing on the known or possible interactions with other drugs. Full-text articles and abstracts were searched in PubMed. EXPERT OPINION: Since prostate cancer occurs mainly in older age, comorbidities and the consequent polypharmacy increase the DDI risk in mHSPC patients who are candidates for ARSI. Waiting for new therapeutic options, in the absence of direct comparisons, pharmacokinetic knowledge is essential to guide clinicians in prescribing ARSI in this setting.
Assuntos
Antagonistas de Receptores de Andrógenos , Interações Medicamentosas , Metástase Neoplásica , Neoplasias da Próstata , Transdução de Sinais , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Antagonistas de Receptores de Andrógenos/farmacocinética , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Polimedicação , Idoso , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/farmacocinética , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/efeitos adversos , Administração Oral , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacologia , AnimaisRESUMO
Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z-endoxifen concentration and tamoxifen treatment outcomes, and identify a Z-endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed-effect (NLME) model for tamoxifen and Z-endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z-endoxifen. The final parent-metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co-medication with CYP2D6 inhibitors, on Z-endoxifen pharmacokinetics. Future work will use the model to simulate Z-endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long-term survival to identify the Z-endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor-positive breast cancer.
Assuntos
Antineoplásicos Hormonais , Neoplasias da Mama , Citocromo P-450 CYP2D6 , Dinâmica não Linear , Tamoxifeno , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacocinética , Tamoxifeno/sangue , Tamoxifeno/uso terapêutico , Humanos , Feminino , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/genética , Neoplasias da Mama/tratamento farmacológico , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/sangue , Modelos Biológicos , Pessoa de Meia-Idade , Estudos de Coortes , Resultado do Tratamento , Simulação por Computador , IdosoRESUMO
Tamoxifen is part of the standard of care of endocrine therapy for adjuvant treatment of breast cancer. However, survival outcomes with tamoxifen are highly variable. The concentration of endoxifen, the 30-100 times more potent metabolite of tamoxifen and bioactivated by the CYP2D6 enzyme, has been described as the most relevant metabolite of tamoxifen metabolism. A genome-wide association study (GWAS) was performed with the objective to identify genetic polymorphisms associated with endoxifen serum concentration levels and clinical outcome in early-stage breast cancer patients receiving tamoxifen. A GWAS was conducted in 608 women of the CYPTAM study (NTR1509/PMID: 30120701). Germline DNA and clinical and survival characteristics were readily available. Genotyping was performed on Infinium Global Screening Array (686,082 markers) and single nucleotide polymorphism (SNP) imputation by using 1000 Genomes. Relapse-free survival during tamoxifen (RFSt) was defined the primary clinical outcome. Endoxifen serum concentration was analyzed as a continuous variable. Several genetic variants reached genome-wide significance (P value: ≤5 × 10-8). Endoxifen concentrations analysis identified 430 variants, located in TCF20 and WBP2NL genes (chromosome 22), which are in strong linkage disequilibrium with CYP2D6 variants. In the RFSt analysis, several SNP were identified (LPP gene: rs77693286, HR 18.3, 95% CI: 15.2-21.1; rs6790761, OR 18.2, 95% CI: 15.5-21.1). Endoxifen concentrations have a strong association with the chromosome 22, which contains the CYP2D6 gene.
Assuntos
Antineoplásicos Hormonais , Neoplasias da Mama , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Tamoxifeno , Humanos , Tamoxifeno/análogos & derivados , Tamoxifeno/uso terapêutico , Tamoxifeno/sangue , Tamoxifeno/farmacocinética , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/sangue , Pessoa de Meia-Idade , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/sangue , Idoso , Citocromo P-450 CYP2D6/genética , Quimioterapia Adjuvante , Adulto , Estadiamento de Neoplasias , Resultado do Tratamento , Intervalo Livre de DoençaRESUMO
Tamoxifen is the most used hormonal therapy for oestrogen receptor-positive breast cancer. CYP2D6 is the main enzyme in the metabolic pathway of tamoxifen to endoxifen. Variations in endoxifen plasma concentrations are associated with CYP2D6 polymorphisms. This study aimed to determine the association between the CYP2D6 polymorphisms and endoxifen plasma concentrations in a cohort of Zimbabwean breast cancer patients (n = 40). TaqMan genotyping and copy number assays were done to determine CYP2D6 genotypes. Tamoxifen and metabolites were quantitated using LC-MS/MS. The population had high frequencies of the CYP2D6 reduced function alleles, *17 (15%) and *29 (18%). The median endoxifen concentration was 4.78 ng/mL, and in 55% of the patients, mostly intermediate metabolizers were below the endoxifen therapeutic threshold of 5.97 ng/mL. The CYP2D6 phenotypes and activity scores were significantly associated with endoxifen plasma concentrations (P = 0.0151) and with endoxifen to N-desmethyl-tamoxifen ratios (P = 0.0006).
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Farmacogenética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Cromatografia Líquida , Zimbábue , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/farmacocinética , Espectrometria de Massas em Tandem , Tamoxifeno/uso terapêutico , Tamoxifeno/farmacocinética , GenótipoRESUMO
Endoxifen (ENDX) is an active metabolite of tamoxifen (TAM), a drug commonly used for the treatment of estrogen receptor-positive breast cancer and metabolized by CYP2D6. Genetic or drug-induced reductions in CYP2D6 activity decrease plasma ENDX concentrations and TAM efficacy. It was proposed that direct oral administration of ENDX would circumvent the issues related to metabolic activation of TAM by CYP2D6 and increase patient response. Here, we characterized the pharmacokinetics and oral bioavailability of ENDX in female rats and dogs. Additionally, ENDX exposure was compared following equivalent doses of ENDX and TAM. ENDX exposure was 100-fold and 10-fold greater in rats and dogs, respectively, with ENDX administration compared with an equivalent dose of TAM. In single-dose administration studies, the terminal elimination half-life and plasma clearance values were 6.3 hours and 2.4 L/h per kg in rats given 2 mg/kg i.v. ENDX and 9.2 hours and 0.4 L/h/kg in dogs given 0.5 mg/kg i.v. ENDX, respectively. Plasma concentrations above 0.1 µM and 1 µM ENDX were achieved with 20-mg/kg and 200-mg/kg doses in rats, and concentrations above 1 µM and 10 µM were achieved with 15-mg/kg and 100-mg/kg doses in dogs. Oral absorption of ENDX was linear in rats and dogs, with bioavailability greater than 67% in rats and greater than 50% in dogs. In repeated-dose administration studies, ENDX peak plasma concentrations reached 9 µM in rats and 20 µM in dogs following four daily doses of 200 mg/kg or 30 mg/kg ENDX, respectively. The results indicate that ENDX has high oral bioavailability, and therapeutic concentrations were maintained after repeated dosing. Oral dosing of ENDX resulted in substantially higher ENDX concentrations than a similar dose of TAM. These data support the ongoing development of ENDX to overcome the limitations associated with CYP2D6-mediated metabolism of TAM in humans. SIGNIFICANCE STATEMENT: This study presents for the first time the pharmacokinetics and bioavailability of endoxifen and three key tamoxifen metabolites following repeated oral dosing in female rats and dogs. This study reports that endoxifen has high oral bioavailability, and therapeutic concentrations were maintained after repeated dosing. On the basis of these data, Z-endoxifen (Z-ENDX) was developed as a drug based upon the hypothesis that oral administration of Z-ENDX would overcome the limitations of CYP2D6 metabolism required for full metabolic activation of tamoxifen.
Assuntos
Neoplasias da Mama , Citocromo P-450 CYP2D6 , Humanos , Feminino , Cães , Ratos , Animais , Citocromo P-450 CYP2D6/metabolismo , Disponibilidade Biológica , Tamoxifeno , Neoplasias da Mama/metabolismo , Antineoplásicos Hormonais/farmacocinéticaRESUMO
Envafolimab (®) is a subcutaneously (SC) administered single domain anti-programmed death ligand 1 (PD-L1) antibody being developed for the treatment of various solid tumours and chronic hepatitis B in China, and for soft tissue sarcomas and biliary tract cancer in the USA. Single-domain antibodies are more soluble and more rapidly penetrate tissues than full monoclonal antibodies, enabling SC administration. Based on the results of a pivotal phase II trial, SC envafolimab was recently approved in China for the treatment of adult patients with previously-treated microsatellite instability-high (MSI-H) or deficient MisMatch Repair (dMMR) advanced solid tumours. This article summarizes the milestones in the development of envafolimab leading to this first approval.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacocinética , China , Aprovação de Drogas , Hepatite B Crônica/tratamento farmacológico , Humanos , Neoplasias/fisiopatologiaRESUMO
Exemestane (EXE) is a hormonal therapy used to treat estrogen receptor-positive breast cancer by inhibiting the final step of estrogen biosynthesis catalyzed by the enzyme aromatase. Cysteine conjugates of EXE and its active metabolite 17ß-dihydro-EXE (DHE) are the major metabolites found in both the urine and plasma of patients taking EXE. The initial step in cysteine conjugate formation is glutathione conjugation catalyzed by the glutathione S-transferase (GST) family of enzymes. The goal of the present study was to identify cytosolic hepatic GSTs active in the GST-mediated metabolism of EXE and 17ß-DHE. Twelve recombinant cytosolic hepatic GSTs were screened for their activity against EXE and 17ß-DHE, and glutathionylated EXE and 17ß-DHE conjugates were detected by ultra-performance liquid chromatography tandem mass spectrometry. GST α (GSTA) isoform 1, GST µ (GSTM) isoform 3 and isoform 1 were active against EXE, whereas only GSTA1 exhibited activity against 17ß-DHE. GSTM1 exhibited the highest affinity against EXE with a Michaelis-Menten constant (KM) value that was 3.8- and 7.1-fold lower than that observed for GSTA1 and GSTM3, respectively. Of the three GSTs, GSTM3 exhibited the highest intrinsic clearance against EXE (intrinsic clearance = 0.14 nl·min-1·mg-1). The KM values observed for human liver cytosol against EXE (46 µM) and 17ß-DHE (77 µM) were similar to those observed for recombinant GSTA1 (53 and 30 µM, respectively). Western blot analysis revealed that GSTA1 and GSTM1 composed 4.3% and 0.57%, respectively, of total protein in human liver cytosol; GSTM3 was not detected. These data suggest that GSTA1 is the major hepatic cytosolic enzyme involved in the clearance of EXE and its major active metabolite, 17ß-DHE. SIGNIFICANCE STATEMENT: Most previous studies related to the metabolism of the aromatase inhibitor exemestane (EXE) have focused mainly on phase I metabolic pathways and the glucuronidation phase II metabolic pathway. However, recent studies have indicated that glutathionylation is the major metabolic pathway for EXE. The present study is the first to characterize hepatic glutathione S-transferase (GST) activity against EXE and 17ß-dihydro-EXE and to identify GST α 1 and GST µ 1 as the major cytosolic GSTs involved in the hepatic metabolism of EXE.
Assuntos
Androstadienos/farmacocinética , Neoplasias da Mama , Glutationa Transferase/metabolismo , Inativação Metabólica/fisiologia , Fígado/enzimologia , Antineoplásicos Hormonais/farmacocinética , Inibidores da Aromatase/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Cromatografia Líquida , Cisteína/metabolismo , Citosol/metabolismo , Estrogênios/biossíntese , Glutationa Transferase/química , Eliminação Hepatobiliar/fisiologia , Humanos , Isoformas de Proteínas , Receptores de EstrogênioRESUMO
The long-term treatment with tamoxifen can alter the lipid profile of patients with breast cancer. Only a few studies associated the plasma concentrations of tamoxifen, endoxifen, and 4-hydroxytamoxifen with blood lipids, which is relevant as the distribution of these compounds for the tissues can be changed, negatively affecting the treatment. The variations in lipids also can account for the high interindividual variation in plasma concentrations of these compounds. The aim of this preliminary study was to associate the plasma levels of tamoxifen and the active metabolites with the lipid levels. An observational study of cases was conducted in patients with breast cancer using tamoxifen in a daily dose of 20 mg. The lipids were measured by spectrophotometric methods and the plasma concentrations of tamoxifen, endoxifen, and 4-hydroxytamoxifen by high-performance liquid chromatography. A total of 20 patients were included in the study. The median plasma concentrations of tamoxifen, 4-hydroxytamoxifen and endoxifen were 62 ng/mL, 1.04 ng/mL and 8.79 ng/mL. Triglycerides levels ranged from 59 to 352 mg/dL, total cholesterol from 157 to 321 mg/dL, LDL-c from 72 mg/dL to 176 mg/dL and HDL-C from 25.1 mg/dL to 62.8 mg/dL. There were no significant associations between the plasma concentrations of tamoxifen, 4-hydroxytamoxifen, and endoxifen with the levels of triglycerides and total cholesterol. The multivariate analysis revealed a weak association between plasma concentrations of tamoxifen and the active metabolites with HDL-c, LDL-c and VLDL-c. This finding provides preliminary evidence of the low impact of lipoproteins levels in the exposure to tamoxifen, 4-hydroxytamoxifen and endoxifen.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Lipídeos/sangue , Tamoxifeno/administração & dosagem , Adulto , Antineoplásicos Hormonais/farmacocinética , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Pessoa de Meia-Idade , Tamoxifeno/análogos & derivados , Tamoxifeno/sangue , Tamoxifeno/farmacocinéticaRESUMO
Dexamethasone (Dex) is a highly insoluble front-line drug used in cancer therapy. Data from clinical trials indicates that the pharmacokinetics of Dex vary considerably between patients and prolonging drug exposure rather than increasing absolute dose may improve efficacy. Non-toxic, fully biodegradable Dex loaded nanovectors (NV) were formulated, via simple direct hydration within 10 min, as a vehicle to extend exposure and distribution in vivo. Dex-NV were just as effective as the free drug against primary human leukemia cells in vitro and in vivo. Importantly, high levels of DMSO solvent were not required in the NV formulations. Broad distribution of NV was seen rapidly following inoculation into mice. NV accumulated in major organs, including bone marrow and brain, known sanctuary sites for ALL. The study describes a non-toxic, more easily scalable system for improving Dex solubility for use in cancer and can be applied to other medical conditions associated with inflammation.
Assuntos
Dexametasona/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas/química , Polímeros/química , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/farmacocinética , Criança , Dexametasona/química , Dexametasona/farmacocinética , Liberação Controlada de Fármacos , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Resultado do Tratamento , Células Tumorais Cultivadas , Adulto JovemRESUMO
PURPOSE: To compare the pharmacokinetics, pharmacodynamics and safety of the new prolonged-release leuprorelin acetate microspheres for injection (3.75 mg) with the reference product Enantone® (3.75 mg). METHOD: 48 healthy male volunteers were enrolled and randomly received a single 3.75 mg dose of the test drug or Enantone®. RESULTS: There were no significant differences in Cmax, AUC0-t and AUC0-48 between the test group and reference group (P > 0.05). The 90% confidence intervals of the two groups were 87.49%~112.74%, 97.15%~154.25%, and 80.85%~109.01%, respectively. Twenty-eight days after administration, both groups reached 100.0% castration level; there was no difference in the time from administration to reaching castration level between the two groups (P > 0.05); However, the difference between the two groups in the duration of castration level was statistically significant (P < 0.05). There were no major or serious adverse events, and the severity was mild to moderate. CONCLUSION: The pharmacokinetic characteristics of leuprorelin in two groups were consistent. The two groups exhibited similar inhibitory effects on testosterone and more subjects in the test group maintained a longer castration time than those in the reference group.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Leuprolida/administração & dosagem , Testosterona/sangue , Adulto , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/farmacologia , Área Sob a Curva , Preparações de Ação Retardada , Humanos , Injeções , Leuprolida/farmacocinética , Leuprolida/farmacologia , Masculino , Microesferas , Método Simples-Cego , Fatores de Tempo , Adulto JovemRESUMO
Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal gland cortex with a heterogeneous but overall dismal prognosis in advanced stages. For more than 50 years, mitotane has remained a cornerstone for the treatment of ACC as adjuvant and palliative therapy. It has a very poor aqueous solubility of 0.1 mg/l and high partition coefficient in octanol/water (log P) value of 6. The commercially available dosage form is 500 mg tablets (Lysodren®). Even at doses up to 6 g/day (12 tablets in divided doses) for several months, > 50% patients do not achieve therapeutic plasma concentration > 14 mg/l due to poor water solubility, large volume of distribution and inter/intra-individual variability in bioavailability. This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the adverse effects but also circumvent the variable oral absorption, give better control over therapeutic plasma mitotane concentration and potentially shorten the time to achieve therapeutic drug plasma concentrations considerably.
Mitotane as tablet form is currently the standard treatment for adrenocortical carcinoma. It has been used for 5 decades but suffers from highly variable responses in patients, subsequent adverse effects and overall lower response rate. This can be fundamentally linked to the exceedingly poor water solubility of mitotane itself. In terms of enhancing water solubility, a few research groups have attempted to develop better formulations of mitotane to overcome the issues associated with tablet dosage form. However, the success rate was limited, and these formulations did not make it into the clinics. In this article, we have comprehensively reviewed the properties of these formulations and discuss the reasons for their limited utility. Furthermore, we discuss a recently developed mitotane nanoformulation that led us to propose a novel approach to mitotane therapy, where intravenous delivery supplements the standard oral administration. With this article, we combine the current state of knowledge as a single piece of information about the various problems associated with the use of mitotane tablets, and herein we postulate the development of a new injectable mitotane formulation, which can potentially circumvent the major problems associated to mitotane's poor water solubility.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Mitotano/administração & dosagem , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Animais , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/farmacocinética , Disponibilidade Biológica , Humanos , Mitotano/química , Mitotano/farmacocinética , Solubilidade , Distribuição TecidualRESUMO
INTRODUCTION: In this research, we used a volumetric absorptive microsampling (VAMS) technique to collect blood samples from the patients. A rapid and simple sample preparation method and LC-MS.MS assay was then developed and validated for the simultaneous analysis of tamoxifen and its three active metabolites. METHODS: VAMS extraction was performed in methanol by sonication-assisted extraction method for 25 min after 2 hof VAMS drying. Separation was carried out using Acquity UPLC BEH C18 column (2.1 x 100 mm; 1.7 µm), with a flow rate of 0.2 mL/min, and the mobile phase gradient of formic acid 0.1% and formic acid 0.1% in acetonitrile for 5 min. The multiple reaction monitoring (MRM) values were set at m/z 358.31>58.27 for N-desmethyltamoxifen, m/z 372.33>72.28 for tamoxifen, m/z 388.22>72.28 for 4-hydroxytamoxifen, m/z 374.25>58.25 for endoxifen, and m/z 260.26>116.12 for propranolol. RESULTS AND DISCUSSION: The lower limit of quantification value (LLOQ) was 2.50 ng/mL for tamoxifen, 2.50 ng/mL for endoxifen, 1.50 ng/mL for 4-hydroxitamoxifen, and 2.00 ng/mL for N-desmethyltamoxifen. Accuracy (%bias) and precision (%CV) were within 20% for LLOQ and 15% for other concentrations. There were no interference responses >20% of the LLOQ and 5% of the internal standard. The level of ion suppression in all analytes was less than 7%. The preparation system developed in this study successfully extracted more than 90% of analytes from the matrix with precision below 15%. Carryover was shown to be below 6% in all analytes. Stability of analytes in VAMS was demonstrated for up to 30 days, under room temperature storage in a sealed plastic bag with desiccant. This method was successfully applied to analyze tamoxifen and the metabolites level in 30 ER+ breast cancer patients.
Assuntos
Antineoplásicos Hormonais/análise , Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/análise , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Reprodutibilidade dos Testes , Tamoxifeno/administração & dosagem , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacocinética , Espectrometria de Massas em Tandem/métodos , Fatores de TempoRESUMO
BACKGROUND: Adjuvant endocrine therapies are known to induce undesirable adverse effects such as vasomotor, vaginal and musculoskeletal symptoms among breast cancer patients. Drugs used in these therapies are often metabolised by cytochrome P450 (CYP) enzymes, in which their metabolising activities can be modified by single nucleotide polymorphisms (SNP) in CYP genes and CYP genotypes. This review aims to explore whether SNPs or genotypes of CYP are associated with the occurrence, frequency and severity of vasomotor, vaginal and musculoskeletal symptoms in breast cancer patients on adjuvant endocrine therapies. METHODS: A literature review was conducted using five electronic databases, resulting in the inclusion of 14 eligible studies, and their findings were presented narratively. Selected items from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist were used for critical appraisal of the reporting quality of the included studies. RESULTS: Most of the included studies showed that SNPs or genotypes of CYP that modify its metabolising activity have no effect on the occurrence, frequency or severity of vasomotor symptoms, including hot flashes. One study showed no correlation of these genetic variations in CYP with musculoskeletal symptoms, and no data were available on the association between such genetic variations and vaginal symptoms. CONCLUSIONS: Overall, genetic variations in CYP have no effect on the experience of hot flashes among breast cancer patients. We recommend exploration of the link between the active metabolites of chemotherapeutic drugs and the molecules shown to affect the occurrence or severity of hot flashes, and the establishment of the relationship between such genetic variations and patients' experience of musculoskeletal and vaginal symptoms. Subgroup analyses based on patients' duration of adjuvant endocrine therapies in such studies are recommended.
Assuntos
Antineoplásicos Hormonais/efeitos adversos , Artralgia/epidemiologia , Neoplasias da Mama/terapia , Sistema Enzimático do Citocromo P-450/genética , Fogachos/epidemiologia , Vagina/patologia , Antineoplásicos Hormonais/farmacocinética , Artralgia/induzido quimicamente , Artralgia/diagnóstico , Artralgia/genética , Atrofia/induzido quimicamente , Atrofia/diagnóstico , Atrofia/epidemiologia , Atrofia/genética , Neoplasias da Mama/genética , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Sistema Enzimático do Citocromo P-450/metabolismo , Antagonistas de Estrogênios/efeitos adversos , Antagonistas de Estrogênios/farmacocinética , Estrogênios/metabolismo , Feminino , Predisposição Genética para Doença , Fogachos/induzido quimicamente , Fogachos/diagnóstico , Fogachos/genética , Humanos , Mastectomia , Estudos Observacionais como Assunto , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Tamoxifeno/efeitos adversos , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacocinética , Vagina/efeitos dos fármacosRESUMO
INTRODUCTION: Mitotane is the only drug registered specifically for adrenocortical carcinoma. Finding the optimal dose for a patient is difficult due to large differences in bioavailability, toxicity and effect. We therefore look to improve personalized dosing of mitotane. AREAS COVERED: We searched PubMed for studies related to mitotane dosing, pharmacokinetics, pharmacogenetics and combination therapy. Comparison of different dosing strategies have not resulted in an optimal advice. Several computerized pharmacokinetic models have been proposed to predict plasma levels. The current pharmacokinetic models do not explain the full variance in plasma levels. Pharmacogenetics have been proposed to find the unexplained variance. Studies on combination therapy have not yet led to a potential dose adjustment for mitotane. EXPERT OPINION: Computerized pharmacokinetics models are promising tools to predict plasma levels, further validation is needed. Pharmacogenetics are introduced in these models, but more research is required before clinical application. We believe that in the near future, personalized mitotane dosage will be aided by a validated web-based pharmacokinetic model with good predictive ability based primarily on clinical characteristics, adjustable for actual plasma levels and dosage.
Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Mitotano/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/farmacocinética , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Mitotano/efeitos adversos , Mitotano/farmacocinética , Modelos Biológicos , Farmacogenética , Medicina de PrecisãoRESUMO
The purpose of this study was to optimize the preparation method of injectable Octreotide microspheres. To explore the correlation between the solvent system and the general properties of microspheres to reduce burst release and enable them to be used for portal hypertension. Octreotide microspheres were prepared by modified double emulsion solution evaporation method after optimizing preparation conditions. The results showed that Octreotide microspheres had a particle size of 57.48 ± 15.24 µm, and the initial release was significantly reduced. In vitro release and in vivo pharmacokinetic data indicated that Octreotide was released stably within 1200 h. The effects on portal vein pressure, liver tissue morphology and other related indexes were observed after administration. As obvious results, injection of Octreotide microspheres could significantly reduce portal vein pressure and reduce the portal vein lumen area in experimental cirrhotic portal hypertensive rats. The optimized Octreotide PLGA microsphere preparation has been proved to have a good effect on PHT in vivo after detecting aminotransferase (AST) and alanine aminotransferase (ALT) activity, liver tissue hydroxyproline (Hyp) content, serum and liver tissue malondialdehyde (MDA) levels, plasma prostacyclin (PGI2) levels, and liver tissue tumor necrosis factor (TNFα) content. In addition, serum and liver tissue superoxide dismutase (SOD) activity and liver tissue glutathione (GSH) content, plasma thromboxane (TXA2), serum nitric oxide (NO), liver tissue nitric oxide synthase (NOS), and plasma and liver tissue endothelin (ET) were significantly increased.
Assuntos
Antineoplásicos Hormonais/farmacologia , Hipertensão Portal/tratamento farmacológico , Microesferas , Octreotida/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacocinética , Química Farmacêutica , Portadores de Fármacos , Testes de Função Hepática , Masculino , Octreotida/administração & dosagem , Octreotida/farmacocinética , Tamanho da Partícula , Ratos , Ratos WistarRESUMO
BACKGROUND: Compared with western countries, Asian breast cancer patients have unique pathological and biological characteristics. Most of them are premenopausal women with HR positive. Tamoxifen as the first-line drug for premenopausal women with HR+ is involved in multiple enzymes and transporters during metabolizing and transporting process. Variants that cause decreased or inactive gene products leading to abnormal responses in tamoxifen therapy have well been studied in western countries, whereas such information is much less reported in Asian populations. OBJECTIVE: In order to elucidate the relationship between genetic variants and tamoxifen-induced individual drug reactions in different Asian populations and further identify genotypes/phenotypes with potential therapeutic significance. METHODS: We reviewed the frequencies of genetic variants in major enzymes and transporter genes involved in the metabolism and transport of tamoxifen across Asian populations as well as significant correlations between genotypes/metabolic phenotypes and metabolites concentrations or BC clinical outcomes. RESULTS: Significant inter-ethnic differences in allele frequencies was found among Asian populations, such as CYP2D6*4, *10, *41, CYP2C9*2, ABCB1 C3435T and SLCO1B1*5, and CYP2D6*10/*10 is the most common genotype correlated with adverse clinical outcomes. Moreover, we summarized the barriers and controversies of implementing pharmacogenetics in tamoxifen therapy and concluded that more population-specific pharmacogenetic studies are needed in the future. CONCLUSION: This review revealed more systematic pharmacogenomics of genes involved in the metabolism and transport besides CYP2D6, are required to optimize the genotyping strategies and guide the personalized tamoxifen therapy in Asian populations.
Assuntos
Antineoplásicos Hormonais/farmacocinética , Povo Asiático/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/etnologia , Tamoxifeno/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Antineoplásicos Hormonais/uso terapêutico , Família 2 do Citocromo P450/genética , Interações Medicamentosas , Frequência do Gene , Genótipo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Menopausa/fisiologia , Farmacogenética , Polimorfismo Genético , Tamoxifeno/uso terapêuticoRESUMO
BACKGROUND: Prostate cancer is the second most common cause of male cancer death after lung cancer in the US. Therefore, there is an urgent need for a highly effective therapeutic drug at substantially low doses. OBJECTIVE: Anti-androgen drug flutamide was delivered to the prostate cancer cells using Papain Mediated Synthesized Gold Nanoparticles (PGNPs) as the drug delivery system. PGNPs and flutamide worked synergistically against cancer cells. METHODS: Flutamide was used to bioconjugate with PGNPs to improve its efficacy against prostate cancer. The synthesis and bioconjugation of flutamide with PGNPs (F-PGNPs) were characterized by various characterization techniques such as UV-vis spectroscopy, Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and zeta potential to ensure the synthesis, size, shape, size distribution, and stability. The drug loading efficiency of flutamide in F-PGNPs was confirmed and validated by UV-vis spectroscopy. Eventually, in vitro studies were performed to determine the potency of F-PGNPs, changes in nuclear morphology, and generation of Reactive Oxygen Species (ROS). RESULTS: The efficacy of F-PGNPs (IC50 is 46.54 µg/mL) was found to be improved significantly over pure flutamide (IC50 is 64.63 µg/mL) against human prostate cancer PC-3 cell line whereas F-PGNPs did not show any significant toxicity up to a fairly high concentration toward normal mouse macrophage J774A.1 cells. The apoptotic effects and ROS generation of F-PGNPs were analyzed by increased permeability of the cell membrane and condensed chromatin with deep blue and green fluorescent nucleus, respectively. DISCUSSION: The results clearly showed that F-PGNPs significantly improved the potency of flutamide by delivering it directly into the nucleus of cancer cells through caveolae-dependent endocytosis. CONCLUSION: Thus, the greater inhibitory effect of F-PGNPs over the pure drug would be of great advantage during prostate cancer treatment.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Flutamida/administração & dosagem , Flutamida/uso terapêutico , Ouro/química , Nanopartículas Metálicas/química , Papaína/química , Antineoplásicos Hormonais/farmacocinética , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Endocitose , Flutamida/farmacocinética , Humanos , Macrófagos/metabolismo , Masculino , Tamanho da Partícula , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/química , Espectrofotometria UltravioletaRESUMO
Introduction: Tamoxifen is still an important drug in hormone-dependent breast cancer therapy. Personalization of its clinical use beyond hormone receptor positivity could improve the substantial variability of the treatment response.Areas covered: The overview of the current evidence for the treatment personalization using therapeutic drug monitoring, or using genetic biomarkers including CYP2D6 is provided. Although many studies focused on the PK aspects or the impact of CYP2D6 variability the translation into clinical routine is not clearly defined due to the inconsistent clinical outcome data.Expert opinion: We believe that at least the main candidate factors, i.e. CYP2D6 polymorphism, CYP2D6 inhibition, endoxifen serum levels may become important predictors of clinical relevance for tamoxifen treatment personalization in the future. To achieve this aim, however, further research should take into consideration more precise characterization of the disease, epigenetic factors and also utilize an appropriately powered multifactorial approach instead of a single gene evaluating studies.
Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/farmacocinética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Citocromo P-450 CYP2D6/genética , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Polimorfismo Genético , Medicina de Precisão , Receptores de Estrogênio/metabolismo , Tamoxifeno/farmacocinética , Resultado do TratamentoRESUMO
Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration-time data for TAM and 6 metabolites come from a prospective, multicenter, 3-year follow-up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients (n = 27,433 concentrations) were analyzed simultaneously with a 7-compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra-rapid metabolizer (UM)), CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N-desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose-adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient's CYP2D6 phenotype for TAM dose adaptation.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Citocromo P-450 CYP2D6/genética , Polimorfismo Genético , Tamoxifeno/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacocinética , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Modelos Biológicos , Variantes Farmacogenômicos , Tamoxifeno/administração & dosagem , Tamoxifeno/análogos & derivados , Tamoxifeno/metabolismoRESUMO
BACKGROUND: Mitotane is the only approved treatment for patients with adrenocortical carcinoma (ACC). A better explanation for the variability in the pharmacokinetics (PK) of mitotane, and the optimization and individualization of mitotane treatment, is desirable for patients. OBJECTIVES: This study aims to develop a population PK (PopPK) model to characterize and predict the PK profiles of mitotane in patients with ACC, as well as to explore the effect of genetic variation on mitotane clearance. Ultimately, we aimed to facilitate mitotane dose optimization and individualization for patients with ACC. METHODS: Mitotane concentration and dosing data were collected retrospectively from the medical records of patients with ACC taking mitotane orally and participating in the Dutch Adrenal Network. PopPK modelling analysis was performed using NONMEM (version 7.4.1). Genotypes of drug enzymes and transporters, patient demographic information, and clinical characteristics were investigated as covariates. Subsequently, simulations were performed for optimizing treatment regimens. RESULTS: A two-compartment model with first-order absorption and elimination best described the PK data of mitotane collected from 48 patients. Lean body weight (LBW) and genotypes of CYP2C19*2 (rs4244285), SLCO1B3 699A>G (rs7311358) and SLCO1B1 571T>C (rs4149057) were found to significantly affect mitotane clearance (CL/F), which decreased the coefficient of variation (CV%) of the random inter-individual variability of CL/F from 67.0 to 43.0%. Fat amount (i.e. body weight - LBW) was found to significantly affect the central distribution volume. Simulation results indicated that determining the starting dose using the developed model is beneficial in terms of shortening the period to reach the therapeutic target and limit the risk of toxicity. A regimen that can effectively maintain mitotane concentration within 14-20 mg/L was established. CONCLUSIONS: A two-compartment PopPK model well-characterized mitotane PK profiles in patients with ACC. The CYP2C19 enzyme and SLCO1B1 and SLCO1B3 transporters may play roles in mitotane disposition. The developed model is beneficial in terms of optimizing mitotane treatment schedules and individualizing the initial dose for patients with ACC. Further validation of these findings is still required.