RESUMO
Monitoring and treating iron overload is crucial in transfusion-dependent thalassaemia patients. Liver stiffness measurement by transient elastography and T2* magnetic resonance imaging represent non-invasive ways to evaluate the adequacy of the iron chelation treatment. We explored the role of single nucleotide polymorphisms involved in vitamin D metabolism, transport and activity, and in deferasirox metabolism on liver iron burden parameters. One-hundred and five beta-thalassaemia patients, treated with deferasirox, have been enrolled. Drug plasma Ctrough and AUC were measured by a HPLC-UV method. Allelic discrimination was performed by real-time PCR. Age, UGT1A1-364 CT/TT and CYP27B1 -1260 GT/TT positively predicted liver stiffness values. Deferasirox dose and serum ferritin negatively predicted T2* data, whereas age and CYP2D6 1457 GG genotype positively influenced these values. The discoveries of this research may be useful for personalized medicine and the proposed method could be applied in patients with hereditary hemochromatosis and myelodysplastic syndromes.
Assuntos
Deferasirox/metabolismo , Ferro/metabolismo , Fígado/metabolismo , Polimorfismo de Nucleotídeo Único , Vitamina D/metabolismo , Talassemia beta/metabolismo , Adulto , Citocromo P-450 CYP2D6/genética , Feminino , Humanos , Desequilíbrio de Ligação , Imageamento por Ressonância Magnética , Masculino , Farmacogenética , Receptores de Calcitriol/genéticaRESUMO
OBJECTIVES: Iron-burden-induced arrhythmia and heart failure are among the leading causes of morbidity and mortality in ß-thalassaemia major patients. T2* cardiac magnetic resonance remains the only reliable noninvasive method for the heart iron excess assessment. We explored the role of single nucleotide polymorphisms involved in vitamin D metabolism, transport and activity and in deferasirox (DFX) metabolism on cardiac iron burden. PATIENTS AND METHODS: One hundred and five ß-thalassaemia patients, treated with DFX, were enrolled in the present study. Drug plasma Ctrough was measured by a high-performance liquid chromatography-ultraviolet method. Allelic discrimination was carried out using the real-time PCR. RESULTS: CYP1A1*1189 CC, ABCG2 421 GA, CYP24A1 8620 GG and VDR TaqI CC single nucleotide polymorphisms influenced T2* values. Age, serum ferritin, ABCG2 421 GA, ABCG2 1194 +928 TC/CC, CYP24A1 22776 TT and VDR TaqI TC/CC were retained in linear regression model. CONCLUSION: Our results suggested, for the first time, the role of DFX and vitamin D pharmacogenetics on cardiac iron overload.
Assuntos
Arritmias Cardíacas/genética , Sobrecarga de Ferro/genética , Vitamina D/genética , Talassemia beta/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Alelos , Arritmias Cardíacas/sangue , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/fisiopatologia , Citocromo P-450 CYP1A1/genética , Deferasirox/administração & dosagem , Deferasirox/efeitos adversos , Feminino , Ferritinas/sangue , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/fisiopatologia , Modelos Lineares , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Vitamina D/metabolismo , Vitamina D3 24-Hidroxilase/genética , Talassemia beta/sangue , Talassemia beta/tratamento farmacológico , Talassemia beta/fisiopatologiaRESUMO
AIM: We explored the role of SNPs within the SLCO1B3, SLCO1B1, SLC22A6, ABCB1, ABCG2, SLCO3A1, CYP2C19, ABCC2, SLC22A1, ABCB11 and NR1I2 genes on voriconazole pharmacokinetics. PATIENTS & METHODS: 233 pediatric patients were enrolled. Drug plasma Ctrough was measured by a HPLC-MS method. Allelic discrimination was performed by qualitative real-time PCR. RESULTS: SLCO1B3 rs4149117 c.334 GT/TT (p = 0.046), ABCG2 rs13120400 c.1194 + 928 CC (p = 0.029) and ABCC2 rs717620 c.-24 GA/AA (p = 0.025) genotype groups significantly influenced Ctrough. ethnicity (p = 0.042), sex (p = 0.033), SLCO1B3 rs4149117 c.334 GT/TT (p = 0.041) and ABCB1 rs1045642 c.3435 TT (p = 0.016) have been retained in linear regression model as voriconazole predictor factors. CONCLUSION: Understanding how some gene polymorphisms affect the voriconazole pharmacokinetic is essential to optimally dose this agent.
Assuntos
Antifúngicos/uso terapêutico , Voriconazol/uso terapêutico , Adolescente , Criança , Feminino , Genótipo , Humanos , Masculino , Proteína 2 Associada à Farmacorresistência Múltipla , Farmacogenética/métodos , Testes Farmacogenômicos/métodos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Voriconazole therapeutic drug monitoring is not consistently recommended due to its high interpatient and intrapatient variability. Here, we aimed to describe our experience with voriconazole for treatment and prophylaxis of invasive fungal infections in paediatric patients. A fully validated high-performance liquid chromatography-mass spectrometry method was used to quantify voriconazole concentration in plasma, at the end of dosing interval. A high interindividual variability was shown. We enrolled 237 children, 83 receiving intravenous and 154 oral voriconazole. A positive correlation between drug dose and drug plasma exposure was observed. Considering intravenous route, patients with higher serum creatinine had higher voriconazole concentrations; a positive correlation was found among drug exposure and age. Sex significantly influenced drug levels: males had higher median drug concentrations than females (P < 0.001). Close voriconazole pharmacokinetics monitoring should help individualize antifungal therapy for children.
Assuntos
Antifúngicos/farmacocinética , Monitoramento de Medicamentos/métodos , Infecções Fúngicas Invasivas/terapia , Voriconazol/farmacocinética , Administração Intravenosa , Administração Oral , Adolescente , Fatores Etários , Antifúngicos/uso terapêutico , Variação Biológica da População , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Creatinina/sangue , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/instrumentação , Feminino , Humanos , Infecções Fúngicas Invasivas/sangue , Masculino , Espectrometria de Massas/instrumentação , Espectrometria de Massas/métodos , Fatores Sexuais , Voriconazol/uso terapêuticoRESUMO
We evaluated the role of deferasirox therapeutic drug monitoring in order to avoid toxicity or treatment failure. Plasma concentrations, measured between two consecutive liver iron determinations, were determined at the end of dosing interval. Fifty-four ß-thalassemic adult patients were enrolled: 50% were males; median age was 32.3 years (IQR 19.1-41.7 years) and median body mass index was 22.25 kg/m2 (IQR 20.24-23.75 kg/m2 ). The mean deferasirox dose was 28.6 ± 6.3 mg/kg/d and mean plasma concentration was 17.3 ± 16.8 µg/mL. Drug levels showed lower results in males. Deferasirox concentration was significantly correlated with serum creatinine levels (P = .01) and serum ferritin (P < .0001). The assessment of deferasirox therapeutic drug monitoring could help clinicians to predict patient responses and to optimize the therapy.
Assuntos
Deferasirox/farmacocinética , Deferasirox/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Talassemia beta/tratamento farmacológico , Adulto , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Quelantes de Ferro/farmacocinética , Quelantes de Ferro/uso terapêutico , Masculino , Adulto JovemRESUMO
OBJECTIVES: Patients with ß-thalassemia major have extremely low vitamin D levels, owing to reduced intestinal absorption, subicteric tint, and/or iron-induced higher pigmentation. We investigated whether some polymorphisms within the VDR, CYP24A1, CYP27B1, and GC genes could play a role in deferasirox pharmacokinetics in a cohort of pediatric patients. PATIENTS AND METHODS: Eighteen children with ß-thalassemia were enrolled. Drug plasma concentrations at the end of dosing interval (Ctrough) and after 0, 2, 4, 6, and 24 h of drug administration were measured by a HPLC-UV method. Allelic discrimination for VDR (TaqI, FokI, BsmI, Cdx2, and ApaI), CYP24A1 (22776, 3999 and 8620), CYP27B1 (2838 and -1260), and GC (1296) single nucleotide polymorphisms was performed by real-time PCR. RESULTS: CYP24A1 8620 AG/GG group negatively predicted Ctrough in regression analysis (P=0.012). ApaI AA genotype resulted as a negative predictor of Ctrough (P=0.025) and area under the concentration curve (P=0.007); FoKI CC genotype remained as area under the concentration curve positive predictor (P=0.008) and TC/CC group as half-life (t1/2) (P=0.003) and volume of distribution (Vd) (P=0.011) negative one; TaqI TC/CC was retained as a negative predictor of drug maximum concentration (Cmax) (P=0.004). Moreover, GC 1296 TG/GG seemed able to predict lower time to reach drug maximum concentration (Tmax) (P=0.033). CONCLUSION: Our preliminary experience suggested the potential usefulness of vitamin D pharmacogenetic to better understand deferasirox interindividual variability, also in pediatric patients.
Assuntos
Benzoatos/farmacocinética , Receptores de Calcitriol/genética , Triazóis/farmacocinética , Vitamina D3 24-Hidroxilase/genética , Talassemia beta/tratamento farmacológico , 25-Hidroxivitamina D3 1-alfa-Hidroxilase , Adolescente , Benzoatos/administração & dosagem , Criança , Pré-Escolar , Deferasirox , Feminino , Humanos , Masculino , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Análise de Regressão , Triazóis/administração & dosagem , Vitamina D/metabolismo , Talassemia beta/genéticaRESUMO
Mortality and morbidity due to invasive fungal infections have increased over the years. Posaconazole is a second-generation triazole agent with an extended spectrum of activity, which shows a high interindividual variability in its plasma levels, rendering dosing in many patients inconsistent or inadequate. Hence, posaconazole therapeutic drug monitoring, which is easily available in clinical practice, may improve treatment success and safety. The aim of the study was to describe posaconazole pharmacokinetics, and to evaluate the utility of therapeutic drug monitoring for therapy and prophylaxis in a cohort of adult patients. A fully validated chromatographic method was used to quantify posaconazole concentration in plasma collected from adult patients at the end of the dosing interval. Associations between variables were tested using the Pearson test. The Mann-Whitney test was used to probe the influence of categorical variables on continuous ones. A high inter-individual variability was shown. Of the 172 enrolled patients, among those receiving the drug by the oral route (N = 170), gender significantly influenced drug exposure: males showed greater posaconazole concentration than females (p = 0.028). This study highlights the importance of therapeutic drug monitoring in those with invasive fungal infections and its significant clinical implications; moreover we propose, for the first time, the possible influence of gender on posaconazole exposure.
RESUMO
OBJECTIVES: Mitotane is the reference drug for the adrenocortical carcinoma treatment; its pharmacological activity seems to depend on drug transformation in two active metabolites: o,p'-DDE (dichlorodiphenylethene) and o,p'-DDA (dichlorodiphenylacetate). Mitotane and metabolites are lipophilic agents; thus, they tend to accumulate into adipose tissues (white and brown), which change their prevalence seasonally. Aim of the work was to evaluate mitotane and metabolites plasma levels variation over the year, in adrenocortical cancer patients treated with Lysodren® for at least 6 months. METHODS: We enrolled a group of 86 adrenocortical carcinoma diagnosed patients, who underwent radical surgery and started mitotane as adjuvant treatment. For drug and metabolites plasma level (from samples collected ~12 h after the dose administration of mitotane, just before the subsequent administration) determination, a validated chromatographic method was used. KEY FINDINGS: Results showed an evidence of a seasonal trend for the three substance (o,p'-DDD, o,p'-DDE and o,p'-DDA) plasma levels, in terms of acrophases and lower values. Furthermore, it came out that male patients need a higher significant mitotane drug dose than female patients to reach mitotane therapeutic window. CONCLUSIONS: In conclusion, this is the first study assessing a mitotane plasma level variation over the year, but further studies in larger cohorts are required.
Assuntos
Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/terapia , Antineoplásicos Hormonais/administração & dosagem , Mitotano/administração & dosagem , Tecido Adiposo/metabolismo , Adulto , Antineoplásicos Hormonais/farmacocinética , Quimioterapia Adjuvante/métodos , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitotano/análogos & derivados , Mitotano/farmacocinética , Estações do Ano , Fatores Sexuais , Fatores de Tempo , Adulto JovemRESUMO
Itraconazole is a first-generation triazole agent with an extended spectrum of activity; it is licensed in adults for superficial and systemic fungal infections; no recommendation has been yet established for use in children patients. Its variable and unpredictable oral bioavailability make it difficult to determine the optimal dosing regimen. Hence, therapeutic drug monitoring, highly available in clinical practice, may improve itraconazole treatment success and safety. The aim of the study was to describe in paediatrics the oral itraconazole pharmacokinetics, used for prophylaxis. Moreover, we evaluated the utility of its therapeutic drug monitoring in this cohort. A fully validated chromatographic method was used to quantify itraconazole concentration in plasma collected from paediatric patients, at the end of dosing interval. Associations between variables were tested using the Pearson test. Mann-Whitney U test has been used to probe the influence of categorical variables on continuous ones. Any predictive power of the considered variables was finally evaluated through univariate and multivariate linear and logistic regression analyses. A high inter-individual variability was shown; ethnicity (beta coefficient, ß -0.161 and interval of confidence at 95%, IC -395.035; -62.383) and gender (ß 0.123 and IC 9.590; 349.395) remained in the final linear regression model with P value of .007 and .038, respectively. This study highlights that therapeutic drug monitoring is required to achieve an adequate target itraconazole serum exposure.
Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Micoses/prevenção & controle , Administração Oral , Antifúngicos/sangue , Antifúngicos/farmacologia , Criança , Pré-Escolar , Feminino , Humanos , Itraconazol/sangue , Itraconazol/farmacologia , MasculinoRESUMO
OBJECTIVES: Iron chelation in the transfusion-dependent anaemias management is essential to prevent end-organ damage and to improve survival. Deferasirox is a once-daily orally active tridentate selective iron chelator which pharmacokinetic disposition could influence treatment efficacy and toxicity. Therapeutic drug monitoring is an important tool for optimizing drug utilization and doses. METHODS: A fully validated chromatographic method was used to quantify deferasirox concentration in plasma collected from paediatric patients with ß-thalassaemia. Samples obtained after 5 days of washout or in naïve patients before and after 2, 4, 6 and 24 h drug administration were evaluated. KEY FINDINGS: Associations between variables were tested using the Pearson test. Twenty paediatric patients were enrolled; they were mainly men (13.65%), with median age of 6.35 years and body mass index of 15.45 kg/m2 . Concerning pharmacokinetic parameters, a higher interindividual variability was shown. A positive, but not significant, correlation (r = 0.363; P = 0.115) was found between deferasirox area under the concentration curve over 24 h (AUC) and drug dose. CONCLUSIONS: Monitoring plasma deferasirox concentrations appears beneficial for guiding appropriate patient treatment, enhancing effectiveness and minimizing toxicity.
Assuntos
Benzoatos/farmacocinética , Benzoatos/uso terapêutico , Quelantes de Ferro/farmacocinética , Quelantes de Ferro/uso terapêutico , Triazóis/farmacocinética , Triazóis/uso terapêutico , Talassemia beta/tratamento farmacológico , Talassemia beta/metabolismo , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Deferasirox , Feminino , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/metabolismo , Masculino , Resultado do TratamentoRESUMO
We present the deferasirox pharmacokinetics evaluation of a female patient on iron chelation, for the interesting findings from her genetic background (hereditary haemochromatosis and heterozygous ß-thalassaemia) and clinical history (ileostomy; iron overload from transfusions). Drug plasma concentrations were measured by an HPLC-UV validated method, before and after ileum resection. Area under deferasirox concentration curve over 24h (AUC) values were determined by the mixed log-linear rule, using Kinetica software. AUC was low also with high deferasirox dose as well as tolerability. Non invasive tissue iron quantification by magnetic resonance imaging or superconducting quantum interference device were prevented by a metal hip replacement. Good efficacy and normalisation of iron markers was obtained on long term. Therapeutic drug monitoring in patient in critical conditions may help to understand reasons for non response and set individualised treatment.
Assuntos
Benzoatos/sangue , Hemocromatose/sangue , Quelantes de Ferro/farmacocinética , Triazóis/sangue , Talassemia beta/sangue , Benzoatos/farmacocinética , Benzoatos/uso terapêutico , Deferasirox , Feminino , Hemocromatose/tratamento farmacológico , Humanos , Quelantes de Ferro/uso terapêutico , Pessoa de Meia-Idade , Triazóis/farmacocinética , Triazóis/uso terapêutico , Talassemia beta/tratamento farmacológicoRESUMO
BACKGROUND: Generic anticancer drugs represent an opportunity in terms of cost savings but there are some concerns about their tolerability. The safety profiles of generic versus branded oxaliplatin formulations have never been studied in detail. PATIENTS AND METHODS: We tested in vitro concentrations, stability and efficacy of branded versus generic oxaliplatin formulations, then we retrospectively collected data about hypersensitivity reactions (HSR) of 427 colorectal cancer patients treated with oxaliplatin-based regimens. RESULTS: No significant difference in oxaliplatin concentration or time-dependent antiproliferative activity between branded and generic oxaliplatin was detected. The incidence of HSR was 12.1% (33/273 patients) in those treated with branded and 9.8% (15/154 patients) in those treated with generic oxaliplatin (p=0.46). The occurrence of grade III-IV HSRs and severe HSRs leading to oxaliplatin discontinuation were comparable. CONCLUSION: No difference between generic and branded formulations of oxaliplatin were demonstrated in preclinical nor in clinical settings. Generic oxaliplatin can be considered a safe alternative to branded formulation.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Medicamentos Genéricos/uso terapêutico , Compostos Organoplatínicos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/etiologia , Medicamentos Genéricos/efeitos adversos , Medicamentos Genéricos/farmacologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Equivalência Terapêutica , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: Deferasirox adverse effects include the following: gastrointestinal disturbance, mild elevations in serum creatinine levels and intermittent proteinuria; these events are dose-dependent and reversible with drug discontinuation, but this solution can lead to an inadequate iron chelation. For these reasons, interindividual variability of drug plasma concentration could help the clinical management of deferasirox dosage. We sought to describe deferasirox plasma exposure in a cohort of 60 adult patients. METHODS: A fully validated chromatographic method was used to quantify deferasirox concentration in plasma collected from ß-thalassaemia adult patients. Samples obtained before and after 2, 4, 6 and 24 h drug administration were evaluated. Associations between variables were tested using the Pearson test. KEY FINDINGS: Concerning pharmacokinetic parameters, a higher interindividual variability was shown. A positive correlation was found between deferasirox area under the concentration curve over 24 h and serum creatinine (r = 0.314; P = 0.018) and between area and drug dose (r = 0.311; P = 0.016). Moreover, a negative correlation resulted among area under the concentration curve over 24 h and serum ferritin (r = -0.291; P = 0.026) and among drug half-life and its dose (r = -0.319; P = 0.013). CONCLUSIONS: Treatment decision based on the individual characteristics could strongly contribute to minimize toxicity and increase efficacy of deferasirox therapy.
Assuntos
Benzoatos/efeitos adversos , Benzoatos/farmacocinética , Quelantes de Ferro/efeitos adversos , Quelantes de Ferro/farmacocinética , Triazóis/efeitos adversos , Triazóis/farmacocinética , Talassemia beta/tratamento farmacológico , Adulto , Área Sob a Curva , Benzoatos/administração & dosagem , Benzoatos/sangue , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Creatinina/sangue , Deferasirox , Monitoramento de Medicamentos/métodos , Feminino , Ferritinas/sangue , Meia-Vida , Humanos , Quelantes de Ferro/administração & dosagem , Masculino , Espectrofotometria Ultravioleta , Triazóis/administração & dosagem , Triazóis/sangue , Talassemia beta/sangue , Talassemia beta/diagnósticoRESUMO
BACKGROUND: Imatinib (Gleevec, STI-571), a 2-phenylaminopyrimidine-type competitive inhibitor of Bcr-Abl kinase, is the current frontline therapy for patients with chronic myeloid leukemia, and it induces durable responses and prolonging event-free and progression-free survival. Monitoring imatinib trough plasma concentration is a simple and rapid way to determine if the drug exposure exceeds the clinical efficacy threshold (1 mcg/mL). Because the target enzyme is located within cells, adequate drug intracellular concentrations are needed to inhibit its function. METHODS: Chromatographic methods were used to quantify imatinib concentrations in both plasma and peripheral blood mononuclear cells collected from adult patients with chronic myeloid leukemia at the Department of Hematology. Samples were collected at steady state, and trough concentrations (24 ± 2 hours after last drug intake) were evaluated. Associations between variables were tested using the Pearson test; results are presented as mean (±SD). RESULTS: Thirty-five samples from 24 patients were collected; patients were mainly men (16, 66.7%), aged 60 years old (±13.1) and with a body mass index of 24.8 (±4.4). A positive and significant correlation (r = 0.203; P = 0.027) was found between imatinib plasma and intracellular concentrations. CONCLUSIONS: The observed correlation between plasma and intracellular imatinib concentrations suggests that they may be used to monitor drug exposure and treatment efficacy.
Assuntos
Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Monitoramento de Medicamentos/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Benzamidas/sangue , Benzamidas/uso terapêutico , Índice de Massa Corporal , Feminino , Humanos , Mesilato de Imatinib , Leucócitos Mononucleares/química , Masculino , Pessoa de Meia-Idade , Piperazinas/sangue , Piperazinas/uso terapêutico , Plasma/química , Pirimidinas/sangue , Pirimidinas/uso terapêuticoRESUMO
OBJECTIVE: The aim of this study was to assess the potential impact of the pharmacogenetic variability of CYP2B6 and ABCB1 genes on the pharmacokinetics of mitotane. METHODS: A retrospective analysis was carried out on 27 patients with adrenocortical carcinoma on postoperative adjunctive mitotane. CYP2B6 and ABCB1 polymorphisms were genotyped and tested for an association with plasma trough concentration after 3, 6, 9, and 12 months of therapy. RESULTS: Patients with the GT/TT genotype had higher mitotane plasma concentrations compared with patients with GG at 3 months (14.80 vs. 8.01 µg/ml; P=0.008) and 6 months (17.70 vs. 9.75 µg/ml; P=0.015). Multivariate logistic regression analysis showed that only the CYP2B6 rs3745274GT/TT genotype (odds ratio=10.7; P=0.017) was a predictor of mitotane plasma concentrations of at least 14 µg/ml after 3 months of treatment. Mitotane concentrations were not influenced by the polymorphisms of the ABCB1 gene. CONCLUSION: Evaluation of the CYP2B6 polymorphism enabled prediction of the individual response to adjuvant mitotane treatment.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Mitotano/farmacocinética , Polimorfismo de Nucleotídeo Único/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Neoplasias do Córtex Suprarrenal/sangue , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/enzimologia , Neoplasias do Córtex Suprarrenal/genética , Adulto , Citocromo P-450 CYP2B6 , Relação Dose-Resposta a Droga , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mitotano/administração & dosagem , Mitotano/sangue , Mitotano/uso terapêutico , Análise MultivariadaRESUMO
We describe a new high performance liquid chromatography coupled with ultraviolet detection method for the quantification of plasma concentration of oral iron chelating agent deferasirox. A simple protein precipitation extraction procedure was applied on 500 µl of plasma aliquots. Chromatographic separation was achieved on a C18 reverse phase column and eluate was monitored at 295 nm, with 8 min of analytical run. This method has been validated following Food and Drug Administration procedures: mean intra and inter day variability was 4.64 and 10.55%; mean accuracy was 6.27%; mean extraction recovery 91.66%. Calibration curves ranged from 0.078125 to 40 µg/ml. Limit of quantification was set at 0.15625 while limit of detection at 0.078125 µg/ml. We applied methodology developed on plasma samples of thalassaemic patients treated with deferasirox, finding correlation between deferasirox plasma concentrations and serum ferritin levels. This methodology allowed a specific, sensitive and reliable determination of deferasirox, that could be useful to perform its therapeutic monitoring and pharmacokinetic studies in patients plasma.
Assuntos
Benzoatos/sangue , Benzoatos/uso terapêutico , Cromatografia Líquida de Alta Pressão/métodos , Talassemia/sangue , Talassemia/tratamento farmacológico , Triazóis/sangue , Triazóis/uso terapêutico , Deferasirox , Feminino , Ferritinas/sangue , Humanos , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estatísticas não ParamétricasRESUMO
Development and validation of simple, rapid, and reliable high-performance liquid chromatography (HPLC)-UV method for quantification of major tyrosine kinase inhibitors, imatinib, dasatinib, and nilotinib, in human plasma is presented. Chromatographic separation of the drugs is achieved on an RP-C(18) column at flow rate of 0.9 mL/min at 35°C; eluate is monitored at 267 nm. Mean intra-day and inter-day precision for all compounds are 2.5 and 13.3%; mean accuracy is 13.9%; extraction recovery ranges within 40.24 and 81.81%. Calibration curves range from 10 to 0.005 µg/mL. Limits of detection are 10 ng/mL for imatinib and nilotinib, 50 ng/mL for dasatinib; limits of quantitation are 50 ng/mL for imatinib and nilotinib, 100 ng/mL for dasatinib. Although this method allows the detection of dasatinib, levels found in patients plasma are close to the limit of detection, then below the limit of quantitation. Quantification with HPLC-mass spectrometry, then, is required for dasatinib to give a correct evaluation. In conclusion, the sensitivity of this new method is sufficient to perform therapeutic monitoring and pharmacokinetic studies of imatinib and nilotinib but not dasatinib in CML patients.
Assuntos
Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Proteínas Tirosina Quinases/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Benzamidas , Dasatinibe , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Modelos Lineares , Piperazinas/sangue , Piperazinas/uso terapêutico , Pirimidinas/sangue , Pirimidinas/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tiazóis/sangue , Tiazóis/uso terapêuticoAssuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Quinidina/análogos & derivados , Administração Oral , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Monitoramento de Medicamentos/métodos , Eletrocardiografia , Feminino , Seguimentos , Humanos , Recém-Nascido , Quinidina/administração & dosagem , Quinidina/farmacocinética , Quinidina/uso terapêuticoRESUMO
A new method using high performance liquid chromatography coupled with electrospray mass spectrometry is described for the quantification of plasma concentration of tyrosine kinase inhibitors imatinib, dasatinib and nilotinib. A simple protein precipitation extraction procedure was applied on 250 microl of plasma aliquots. Chromatographic separation of drugs and Internal Standard (quinoxaline) was achieved with a gradient (acetonitrile and water + formic acid 0.05%) on a C18 reverse phase analytical column with 20min of analytical run, at flow rate of 1 ml/min. Mean intra-day and inter-day precision for all compounds were 4.3 and 11.4%; mean accuracy was 1.5%; extraction recovery ranged within 95 and 114%. Calibration curves ranged from 10,000 to 62.5 ng/ml. The limit of quantification was set at 78.1 ng/ml for imatinib and at 62.5 ng/ml for dasatinib and nilotinib. This novel developed methodology allows a specific, sensitive and reliable simultaneous determination of the three tyrosine kinase inhibitors imatinib, dasatinib and nilotinib in a single chromatographic run, useful for drugs estimation in plasma of patients affected by chronic myeloid leukemia.
Assuntos
Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Espectrometria de Massas/métodos , Piperazinas/sangue , Inibidores de Proteínas Quinases/sangue , Pirimidinas/sangue , Tiazóis/sangue , Benzamidas , Calibragem , Dasatinibe , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Sensibilidade e EspecificidadeRESUMO
A new C18 reversed-phase column and UV HPLC method for the detection of mitotane, its principal metabolites, dichlorodiphenylacetate and dichlrodiphenylethene, and its precursor DDT is described. In this article mitotane, dichlorodiphenylacetate, and dichlrodiphenylethene concentrations in organs of rats fed on a mitotane diet, and the effects of erythromycin and grapefruit juice as cytochrome P450 common inhibitors are presented. Tissue accumulation of mitotane and dichlrodiphenylethene, the acquired ability to eliminate dichlorodiphenylacetate, and inhibition of beta-hydroxylation by both inhibitors are illustrated here. Blood samples from mitotane-treated patients revealed two correlations: plasma mitotane/dichlrodiphenylethene and plasma mitotane/red cell mitotane.