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BACKGROUND: An inexpensive, simple, and accurate plasma concentration measurement system is needed to actively conduct pharmacokinetic and pharmacodynamic analyses of vadadustat, hypoxia-inducible factor-prolyl hydroxylase inhibitor, in clinical settings. In this study, the authors aimed to develop a method for measuring vadadustat in human plasma that could be applied for therapeutic drug monitoring using high-performance liquid chromatography with ultraviolet detection (HPLC-UV) in a clinical setting. METHODS: Plasma samples (100 µL) were pretreated with acetonitrile using butyl paraoxybenzoate as an internal standard. Chromatographic separation was performed on a SunShell PFP C18 column (2.6 µm, 4.6 mm × 150 mm). The mobile phase consisted of (A) 20 mM of phosphate buffer (pH 2.4) and (B) acetonitrile (60:40, v/v), delivered isocratically at a flow rate of 1 mL/min. The analytes were detected by UV absorbance at a wavelength of 220 nm, and the column temperature was 40°C. To evaluate the applicability of HPLC-UV in a clinical setting, blood samples were collected at 19 time points from 7 patients who had been taking vadadustat. RESULTS: The calibration curve was linear over the concentration range of 0.2-150 mcg/mL (R2 > 0.99). Intra-assay and interassay accuracy, precision, and stability met the Food and Drug Administration recommendations. The vadadustat plasma concentrations of patients analyzed using the current HPLC-UV method were almost equal to those measured using ultra-performance liquid chromatography-tandem mass spectrometry (mean difference: 0.13 mcg/mL). Large variability in the dose-adjusted plasma concentrations of vadadustat at 12 hours after administration was observed between patients (coefficient of variation = 57.6%). CONCLUSIONS: This HPLC-UV method is a simple, accurate quantification method for evaluating plasma concentrations in patients taking vadadustat in a clinical setting.
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INTRODUCTION: The authors aimed to examine the impact of single nucleotide polymorphisms in P-glycoprotein, the hepatic uptake transporter organic anion transporter protein 1B1, cytochrome P450 ( CYP ) 3A5, and carboxylesterase-1 ( CES1 ) on the steady-state dose-adjusted trough concentrations of edoxaban (C Edo /D) and M-4 (C M-4 /D). They also investigated whether C M-4 and C Edo affect prothrombin time (PT). METHODS: The analyses included 152 patients with nonvalvular atrial fibrillation (NVAF) undergoing AF catheter ablation. The CYP3A5*3 ; CES1 c.1168-33A>C, c.257+885T>C; SLCO1B1 c.388A>G, c.521T>C; and ABCB1 c.3435C>T, c.2677G>A/T, c.1236C>T genotypes were determined. RESULTS: Stepwise selection multiple linear regression analyses demonstrated that creatinine clearance (Ccr), concomitant use of amiodarone, and SLCO1B1*15 haplotype status were independent factors influencing C M-4 /D (partial R2 = 0.189, 0.098, 0.067, respectively, all P values < 0.005). Ccr and concomitant use of amiodarone were independent factors influencing C Edo /D (partial R2 = 0.260, 0.117, respectively, both P value < 0.001). C Edo and C M-4 showed a weak correlation with PT (ρ = 0.369 and 0.315, both P values < 0.001). CONCLUSIONS: Although information concerning Ccr, concomitant use of amiodarone, and SLCO1B1*15 haplotype may be useful in assessing the pharmacokinetics of edoxaban, further studies are needed to clarify the requirement of PT monitoring at the trough level for dose adjustment of edoxaban in patients with NVAF.
Assuntos
Amiodarona , Fibrilação Atrial , Humanos , Haplótipos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/genética , Tempo de Protrombina , Transportador 1 de Ânion Orgânico Específico do Fígado/genéticaRESUMO
PURPOSE: We examined the impact of polymorphisms in genes encoding cytochrome P450 (CYP) 3A5 (gene code CYP3A5), P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), cytochrome P450 oxidoreductase (POR), and pregnane X receptor (PXR; NR1I2) on the daily dose-adjusted steady-state trough concentrations (C0h/D) of apixaban. METHODS: The analyses included 104 patients with non-valvular atrial fibrillation (NVAF) undergoing AF catheter ablation. The CYP3A5*3; ABCG2 421C > A; ABCB1 1236C > T, 2677G > A/T, 3435C > T, and 2482-2236G > A; NR1I2 11156A > C, 11193T > C, and 8055C > T; and POR*28 genotypes were determined. The combination of the noted NR1I2 genotypes determined the PXR*1B haplotype. RESULTS: Multiple linear regression analyses demonstrated that decreased creatinine clearance (Ccr) and the PXR*1B/*1B haplotype correlated with increased C0h/D of apixaban, while the presence of the POR*28 allele correlated with decreased C0h/D of apixaban (partial R2 = 0.168, 0.029, and 0.044, all P < 0.05). The mean (95% CI) of estimated marginal means of apixaban C0h/D calculated using Ccr as a covariate was the highest in POR*28 noncarriers with PXR*1B/*1B (23.5 [21.0-25.9] ng/mL/[mg/day]) and lowest in POR*28 carriers with other haplotypes (16.6 [15.5-17.7] ng/mL/[mg/day]). CONCLUSION: The PXR*1B haplotype and POR*28 genotype statuses, which involve genes that impact the expression of multiple drug-metabolizing enzymes and drug-transporters, may have modest effects on the C0h/D of apixaban, but these effects were found to be small.
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Fibrilação Atrial , Citocromo P-450 CYP3A , Humanos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Receptor de Pregnano X/genética , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Neoplasias/genética , Polimorfismo Genético , Genótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Trimethoprim (TMP) inhibits the Na+ /K+ -ATPase present in the basement membrane of distal tubular epithelial cells. However, hyponatremia and hyperkalemia may develop in patients taking TMP-sulfamethoxazole (SMX). In addition, because TMP inhibits drug transporters, such as organic cation transporter 2 and multidrug and toxin extrusion protein 2-K in proximal tubules, reversible increases in the concentration of serum creatinine (SCr), the substrate of these transporters, may occur. Here, we investigated variability in SCr, serum sodium (Na+ ), and serum potassium (K+ ) concentrations after initiation of TMP-SMX treatment and evaluated the risk of hyponatremia and hyperkalemia in patients with increased SCr concentrations without changes in the glomerular filtration rate (GFR). METHODS: In this retrospective study, all patients aged 20 years or older who received oral TMP-SMX during hospitalization were enrolled. The patients with estimated creatinine (Cr) clearance (eCCr) lower than 30 mL/min were excluded, as were patients taking drugs that were likely to induce renal dysfunction, drugs other than glucocorticoids that were likely to induce electrolyte imbalances, or drugs other than TMP that inhibit tubular Cr secretion. Additionally, those with SCr concentrations elevated more than 30% from baseline or serum blood urea nitrogen concentration levels above 20 mg/dL during follow-up were also excluded. RESULTS AND DISCUSSION: In total, 111 patients were enrolled in the study. The common independent variable affecting the change rate in SCr, Na+ , and K+ concentrations (ΔSCr, ΔNa+ , and ΔK+ ) from baseline to the highest value during the follow-up period (14 days after initiation of TMP-SMX treatment) was the daily dose of TMP. There were significant correlations between ΔSCr and ΔNa+ or ΔK+ (ρ = -0.199, p = 0.036 and ρ = 0.244, p = 0.010, respectively). Kaplan-Meier curves for hyponatremia and hyperkalemia with greater than or equal to grade 1 severity showed different profiles when the TMP dose varied (≤ 160 vs. > 160 mg/day; p = 0.005 and 0.008). The cumulative incidences of both adverse effects were 64.7% (median: 7 days) and 29.4% in patients taking more than 160 mg/day TMP and 35.2% and 6.7% in patients taking 160 mg/day TMP or less. Thus, TMP may affect the kinetics of Cr, Na+ , and K+ in the proximal and distal tubules in a dose-dependent without changing the GFR. WHAT IS NEW AND CONCLUSION: This study is the first report to demonstrate the degree of changes in SCr, Na+ , and K+ concentrations after initiation of TMP-SMX treatment. If SCr is elevated after initiation of TMP-SMX treatment, clinicians should be aware of decreased Na+ and increased K+ concentrations. TMP may increase the risks of hyponatremia and hyperkalemia in a dose-dependent manner without altering GFR.
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Hiperpotassemia , Hiponatremia , Adenosina Trifosfatases , Creatinina , Eletrólitos , Taxa de Filtração Glomerular , Glucocorticoides , Humanos , Hiperpotassemia/induzido quimicamente , Hiponatremia/induzido quimicamente , Transportador 2 de Cátion Orgânico , Potássio , Estudos Retrospectivos , Sódio , Combinação Trimetoprima e Sulfametoxazol/efeitos adversosRESUMO
BACKGROUND: The authors conducted a phase II clinical trial of lenalidomide and dexamethasone combination therapy in Japanese elderly patients with newly diagnosed multiple myeloma to evaluate its safety and efficacy and to determine whether safety and efficacy correlate with the plasma concentration of lenalidomide. METHODS: Forty patients received oral lenalidomide on days 1-21 of a 28-day cycle in addition to weekly doses of dexamethasone. Plasma concentrations of lenalidomide were measured, and the area under the concentration-time curve from 0 to 24 hours (AUC0-24) of lenalidomide was predicted using a formula the authors previously reported in this journal. RESULTS: The median age was 75.5 years. Twenty-one patients had renal impairment severe enough to require dose adjustment of lenalidomide. The median initial doses of lenalidomide and dexamethasone were 12.5 and 20 mg, respectively. The overall response rate was 68.6%, and the 2-year overall survival rate was 88.5%. There was no correlation between the response rate and plasma concentration of lenalidomide. Grade 3-4 adverse events (AEs) were observed in 57.5% of patients. The AUC0-24 of lenalidomide was significantly higher in patients with grade 3-4 AEs than in those who did not suffer from AEs (median = 4852.0 versus 2464.9 ng·h·mL, P = 0.027). Receiver-operating characteristic curve analysis showed that the AUC0-24 of lenalidomide was a good predictor of grade 3-4 AEs, with an area under the receiver-operating characteristic curve of 0.758 (95% confidence interval, 0.572-0.943, P = 0.027). The cutoff value for best prediction of grade 3-4 AEs was 2613.5 ng·h·mL (sensitivity 86.7%, specificity 54.5%). Multivariate logistic analysis confirmed the significance of this cutoff value. CONCLUSIONS: These data suggest that overexposure to lenalidomide could contribute to toxicity. Furthermore, the predicted cutoff value of AUC0-24 can be clinically used to prevent severe AEs.
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Dexametasona/administração & dosagem , Dexametasona/sangue , Lenalidomida/administração & dosagem , Lenalidomida/sangue , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/sangue , Dexametasona/efeitos adversos , Monitoramento de Medicamentos/métodos , Quimioterapia Combinada , Feminino , Seguimentos , Doenças Hematológicas/induzido quimicamente , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/sangue , Japão/epidemiologia , Lenalidomida/efeitos adversos , Masculino , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/epidemiologia , Resultado do TratamentoAssuntos
Fibrilação Atrial , Acidente Vascular Cerebral , Humanos , Rivaroxabana/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/genética , Receptor de Pregnano X/genética , Sistema Enzimático do Citocromo P-450 , Anticoagulantes/uso terapêutico , Inibidores do Fator Xa/uso terapêuticoRESUMO
While tacrolimus and everolimus have common metabolic pathways through CYP3A4/5, tacrolimus is metabolized solely by CYP3A4 in recipients with the CYP3A5*3/*3. The purpose of this study was to evaluate how the area under the blood concentration-time curves (AUC) of tacrolimus could be predicted based on CYP3A5 genotype and the AUC of everolimus in renal transplant patients taking both drugs. The dose-adjusted AUC (AUC/D) of tacrolimus and everolimus were calculated at one month and one year after transplantation. Significant correlations between the AUC/D of tacrolimus and everolimus were found for patients with the CYP3A5*1 allele or CYP3A5*3/*3 at both one month and one year. At both stages, the determination coefficients were higher and the slopes of regression equations were larger for patients with CYP3A5*3/*3 compared to the CYP3A5*1 allele. A good correlation between single doses of tacrolimus and everolimus was found for CYP3A5*3/*3 patients at 1 year after transplantation (r = 0.794, p < 0.001). The variability of the AUC0-24/D of tacrolimus for each CYP3A5 genotype could be predicted based on the AUC0-12/D of everolimus. Clinicians may be able to comprehensively carry out the dose adjustments of tacrolimus and everolimus based on relationship with AUCs of both drugs in each CYP3A5 genotype.
Assuntos
Inibidores de Calcineurina/sangue , Citocromo P-450 CYP3A/genética , Everolimo/sangue , Imunossupressores/sangue , Transplante de Rim , Tacrolimo/sangue , Alelos , Área Sob a Curva , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/farmacocinética , Quimioterapia Combinada , Everolimo/administração & dosagem , Everolimo/farmacocinética , Feminino , Genótipo , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Fatores de Tempo , TransplantadosRESUMO
BACKGROUND: The present study investigated interstitial fibrosis (IF) in 144 kidney recipients 0 h and 1 year post transplantation and assessed relationships with Banff code scores, clinical parameters, and long-term graft function. METHODS: A quantitative analysis of IF was performed using the computer-assisted imaging of Sirius red-stained biopsy samples. Percent IF (%IF) in the cortical region was assessed at 0 h and 1 year, and an increase in the ratio of %IF from 0 h to 1 year was calculated. The relationship between %IF and Banff code scores was analyzed. Demographics and trough concentrations of tacrolimus were tested as risk factors in the top 20 patients with increases in %IF. The influence of increases in the ratio of %IF at 1 year on long-term graft function and survival was also assessed in these 20 patients. RESULTS: Median %IF at 0 h and 1 year were 1.55 and 2.80%, respectively. No correlation was found between %IF and Banff code scores. The mean increase in the ratio of %IF from 0 h to 1 year was 4.31-fold. The increase in %IF in the top 20 patients correlated with diabetes mellitus. Graft function, but not graft survival, was lower in the top 20 patients for 10 years post transplantation. CONCLUSIONS: A correlation was not found between %IF and Banff code scores. Greater increases in %IF within 1 year post transplantation may influence long-term graft survival. Computer-analyzed increases in %IF at 1 year may be a surrogate marker for long-term graft function.
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Aloenxertos/patologia , Sobrevivência de Enxerto , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Rim/patologia , Adulto , Idoso , Atrofia , Compostos Azo/química , Biópsia , Corantes/química , Feminino , Fibrose , Imunofluorescência/métodos , Taxa de Filtração Glomerular , Humanos , Processamento de Imagem Assistida por Computador , Rim/cirurgia , Masculino , Pessoa de Meia-Idade , Coloração e Rotulagem/métodos , Fatores de Tempo , Transplante Homólogo/efeitos adversos , Adulto JovemRESUMO
Although sunitinib is a well-established chemotherapeutic for metastatic renal cell carcinoma (mRCC), there are no robust markers that predict efficacy and toxicity. We analyzed the effect of single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics on clinical outcomes in Japanese patients with mRCC. We analyzed the effect of SNPs in genes involved in sunitinib pharmacokinetics on the clinical outcome in mRCC patients in a Japanese population. We evaluated seven SNPs in four candidate genes, the transport proteins ATP-binding cassette (ABC) B1 (rs1045642, rs1128503, rs2032582, and rs7779562) and ABCG2 (rs2231142), and the metabolic proteins cytochrome P450 (CYP) 3A4 (rs35599367) and CYP3A5 (rs776746) in 70 patients. No significant association was observed between the genotypes of each SNP and time to dose reduction, progression-free survival, overall survival, and best objective response. Meanwhile, the incidence of grade 2 or greater hypertension and hand-foot syndrome, and multiple adverse events (>3), was significantly higher in patients carrying the ABCB1 rs2032582 GG genotype [odds ratio (OR): 5.37, 95% confidence interval (CI) 1.02-14.63, P=0.035; OR: 3.17, 95% CI 1.06-9.52, P=0.036, OR: 3.35; 95% CI 1.14-9.84; P=0.025, respectively]. In conclusion, our data showed that the ABCB1 rs2032582 GG genotype was associated with individual adverse events' susceptibility among Japanese patients treated with sunitinib in routine clinical settings.
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Povo Asiático/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Indóis/farmacocinética , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Pirróis/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Feminino , Humanos , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Polimorfismo de Nucleotídeo Único , Pirróis/uso terapêutico , SunitinibeRESUMO
BACKGROUND: Although voriconazole (VRCZ) is metabolized to VRCZ N-oxide principally by CYP2C19, VRCZ clearance is affected by multiple factors. In this study, we investigated the relationship between the CYP2C19 phenotype using the VRCZ-to-VRCZ N-oxide plasma concentration ratio (VRCZ/N-oxide) and demographic and clinical characteristics of Japanese patients taking VRCZ. METHODS: A total of 65 Japanese patients taking VRCZ for prophylaxis or treatment of fungal infection were enrolled in this study. Stepwise selection multiple linear regression analysis was performed to investigate the effect of factors on the VRCZ/N-oxide ratio. RESULTS: In patients not undergoing concurrent treatment with a drug influencing CYP2C19 activity (n = 54), the VRCZ/N-oxide ratio with definite thresholds for CYP2C19 genotypes, CYP2C19*1/*1, *1/*2 + *1/*3 + *2/*17, and *2/*2 + *2/*3, was specifically identified in patients taking VRCZ (<0.48, ≥0.48 < and <0.82 and ≥0.82). However, the VRCZ/N-oxide ratio could not be predicted based solely on the CYP2C19 genotype (R = 0.053). The route of VRCZ administration, C-reactive protein concentration determined on the same day as VRCZ plasma concentration measurement, CYP2C19 extensive metabolizer, and patient age were independent factors influencing the VRCZ/N-oxide ratio (R = 0.489, standardized regression coefficient = 0.385, 0.380, -0.231, and 0.231; P = 0.001, 0.001, 0.032, and 0.036, respectively). CONCLUSIONS: It is possible to comprehensively evaluate CYP2C19 activity using the actual measured value of the VRCZ/N-oxide ratio in patients taking VRCZ. The predictive performance of the VRCZ/N-oxide ratio was improved by including the route of administration, C-reactive protein level, and patient age in addition to the CYP2C19 genotype as predictive factors.
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Antifúngicos/sangue , Citocromo P-450 CYP2C19/genética , Óxidos/sangue , Voriconazol/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Proteína C-Reativa/metabolismo , Demografia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético/genética , Adulto JovemRESUMO
1. The objective of this study was to examine the association of UGT1A9, SLCO, and ABCC polymorphisms with mycophenolic acid (MPA) pharmacokinetics in ABO blood type (ABO) incompatible patients with severe renal dysfunction pre-transplantation. 2. In all patients, on day 14 after beginning mycophenolate mofetil (MMF) treatment (1 week before transplantation) and on day 28 after renal transplantation, samples were collected just prior to and 1, 2, 3, 4, 6, 9, and 12 h after oral MMF administration. 3. The median dose-adjusted AUC0-12 of MPA after renal transplantation was significantly lower than before transplantation (57.9 versus 76.5 µg h/mL, respectively, p = 0.002). 4. Although the enterohepatic circulation of MPA pre-transplantation was extremely high (57.6%), this level was significantly reduced after renal transplantation (34.6%). 5. In the multivariate analysis, pre-transplantation, patients with the SLCO1B3 334T allele (p = 0.003), higher alanine aminotransferase (p = 0.002), and lower body weight were independently predictive for a higher dose-adjusted AUC0-12 of MPA. 6. In patients with severe renal dysfunction pre-transplantation, MPA is excreted mainly to bile from the liver, and as a consequence, the SLCO1B3 334T > G polymorphism was found to be significantly associated with MPA exposure.
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Imunossupressores/farmacocinética , Transplante de Rim , Ácido Micofenólico/farmacocinética , Área Sob a Curva , Feminino , Glucuronosiltransferase/genética , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , UDP-Glucuronosiltransferase 1ARESUMO
BACKGROUND: We investigated the impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations (C 0h/D) and the incidence of rejection in Japanese recipients taking twice-daily (Tac-BID, n = 140) or modified-release once-daily (Tac-QD, n = 80) tacrolimus formulations for 1 year after renal transplantation. METHODS: Logistic regression analysis was carried out to estimate the distinction rate of CYP3A5 genotypes based on the C 0h/D of Tac-BID or Tac-QD. The coefficients of variation (%CVs) were compared in each recipient to estimate the stability of tacrolimus C 0h/D between formulations or CYP3A5 genotypes. RESULTS: Recipients with at least one CYP3A5*1 wild-type allele (EMs) and recipients with homozygous expression of the variant allele CYP3A5*3 (PMs) were significantly identified using the tacrolimus C 0h/D cut-off values of 2.77 and 0.85 ng/mL/mg, respectively, and discrimination rates of 75.3 and 85.4%, respectively, for Tac-BID and Tac-QD groups. The %CV of the tacrolimus C 0h/D in CYP3A5 EMs taking Tac-QD was significantly lower than that in those taking Tac-BID (20.4 versus 23.3%, P = 0.003). The %CV of the tacrolimus C 0h/D was an independent risk factor for rejection (odds ratio = 1.028, P = 0.033). CONCLUSIONS: The tacrolimus C 0h/D values with definite cut-offs for CYP3A5 genotypes were specifically identified in Japanese renal transplant recipients taking Tac-QD. In addition, a larger %CV for the tacrolimus C 0h/D correlated with the incidence of rejection. Consequently, the stability of the C 0h/D achieved using Tac-QD, which was clearly influenced by the CYP3A5 polymorphism, may prevent the development of rejection.
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Inibidores de Calcineurina/administração & dosagem , Citocromo P-450 CYP3A/genética , Rejeição de Enxerto/prevenção & controle , Imunossupressores/administração & dosagem , Transplante de Rim , Variantes Farmacogenômicos , Tacrolimo/administração & dosagem , Povo Asiático/genética , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/sangue , Inibidores de Calcineurina/farmacocinética , Distribuição de Qui-Quadrado , Citocromo P-450 CYP3A/metabolismo , Composição de Medicamentos , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Genótipo , Rejeição de Enxerto/etnologia , Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Imunossupressores/farmacocinética , Incidência , Japão/epidemiologia , Transplante de Rim/efeitos adversos , Modelos Logísticos , Análise Multivariada , Razão de Chances , Farmacogenética , Fatores de Risco , Tacrolimo/efeitos adversos , Tacrolimo/farmacocinética , Resultado do TratamentoRESUMO
OBJECTIVES: To examine whether a trough concentration of everolimus in the therapeutic range of 3-5 ng/mL affects the pharmacokinetics of tacrolimus in renal transplant patients. METHODS: A total of 52 Japanese renal transplant patients receiving tacrolimus were enrolled in this study. In 28 of them, everolimus was co-administered on day 14 after surgery. Changes in the dose-adjusted blood trough concentration of tacrolimus from day 14 to 28 after surgery were investigated. RESULTS: The dose-adjusted blood trough concentration of tacrolimus on day 28 was affected by CYP3A5*3/*3 and hemoglobin level (P < 0.001 and P = 0.007), but not by everolimus (P = 0.171). In addition, there was no change in the dose-adjusted blood trough concentration of tacrolimus in patients before or after everolimus coadministration (P = 0.165). On day 28, there was no correlation between the rate of change in the dose-adjusted blood trough concentration of tacrolimus and the blood trough concentration or area under the plasma concentration-time curve from 0 to 12 h for everolimus after initiation of combination therapy (r = 0.341, P = 0.076 and r = 0.234, P = 0.231). CONCLUSIONS: A pharmacokinetic interaction between tacrolimus and everolimus was not observed clinically in renal transplant patients. Safe and reliable immunosuppressive therapy in renal transplant patients might be achieved using a combination of tacrolimus and everolimus.
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Everolimo/farmacologia , Imunossupressores/farmacocinética , Transplante de Rim , Tacrolimo/farmacocinética , Área Sob a Curva , Citocromo P-450 CYP3A , Genótipo , Humanos , Imunossupressores/farmacologiaRESUMO
PURPOSE: The aim of this study was to investigate the effect of itraconazole (ITCZ), a potent inhibitor of CYP3A4 and P-glycoprotein, on the blood concentration 12 h after tacrolimus administration (C 12h) in relation to CYP3A5 6986A>G and ABCB1 3435C>T genotype status in patients with connective tissue disease (CTD). METHODS: Eighty-one CTD patients taking tacrolimus (Prograf®) once daily at night (2100 hours) were enrolled in this study. Whole blood samples were collected 12 h after tacrolimus administration at steady state. RESULTS: The dose-adjusted tacrolimus C 12h with or without ITCZ co-administration was significantly higher in patients with CYP3A5*3/*3 than in those with the CYP3A5*1 allele [CYP3A5 *1/*1 vs. *1/*3 vs. *3/*3 = 1.67 vs. 2.70 vs. 4.83 ng/mL/mg (P = 0.003) and 0.68 vs. 0.97 vs. 2.20 ng/mL/mg (P < 0.001), respectively], but differences were not observed for ABCB1 genotypes. However, there was no difference in the increase rate of the dose-adjusted C 12h of tacrolimus between CYP3A5 or ABCB1 genotypes (P = 0.378 and 0.259). On the other hand, reduction of the estimated glomerular filtration rate exhibited a correlation with the C 12h of tacrolimus after ITCZ co-administration (r = -0.482, P = 0.009). CONCLUSIONS: In CYP3A5*3/*3 patients, because the metabolic pathway for tacrolimus occurs only through CYP3A4, the combination with ITCZ seems to lead to a higher risk of acute renal dysfunction. Therefore, we suggest that the target blood tacrolimus concentration be set as low as possible through dose-adjustment for patients with the CYP3A5*3/*3 allele.
Assuntos
Doenças do Tecido Conjuntivo/genética , Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , Itraconazol/farmacologia , Polimorfismo de Nucleotídeo Único/genética , Tacrolimo/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Idoso , Doenças do Tecido Conjuntivo/tratamento farmacológico , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Feminino , Genótipo , Humanos , Imunossupressores/sangue , Itraconazol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Tacrolimo/administração & dosagem , Tacrolimo/sangue , Adulto JovemRESUMO
1. The purpose of the present study was to investigate the effect of tacrolimus concentration in blood 12 h after administration (C12h) on acute renal dysfunction in patients with lupus nephritis (LN) taking tacrolimus once daily. 2. Five of the 35 LN patients experienced tacrolimus-induced acute renal dysfunction. 3. The average annual C12h of tacrolimus was higher for patients with events of elevated serum creatinine level than for patients not experiencing these events [6.4 (5.6-8.8) versus 2.8 (2.2-4.6) ng/mL, respectively, p=0.001]. 4. The average annual tacrolimus C12h was higher for patients with CYP3A5*3/*3 (PM) than for patients with the CYP3A5*1 allele (EM) [4.6 (3.2-6.6) versus 2.5 (2.0-3.1) ng/mL, respectively, p=0.002]. 5. The area under the receiver operating characteristic was 0.887, which gave the best sensitivity (80.0%) and specificity (86.7%) at a tacrolimus C12h (average annual C12h or C12h at events) threshold of 5.2 ng/mL. 6. C12h measurements, CYP3A5 genotyping and dose adjustments of tacrolimus should be performed to prevent acute renal dysfunction in LN patients taking tacrolimus once daily.
Assuntos
Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Imunossupressores/efeitos adversos , Nefropatias/induzido quimicamente , Nefrite Lúpica/complicações , Tacrolimo/efeitos adversos , Adolescente , Adulto , Idoso , Área Sob a Curva , Creatinina/sangue , Feminino , Genótipo , Humanos , Imunossupressores/farmacocinética , Estimativa de Kaplan-Meier , Nefropatias/complicações , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Tacrolimo/farmacocinética , Adulto JovemRESUMO
While CYP3A5 polymorphisms are used to predict the initial dosage of tacrolimus therapy, the predictive capability of genetic information for dosing at early stage post-renal transplantation is unknown. We investigated the influence of polymorphisms over time. An initial oral dose of modified-release once-daily tacrolimus formulation (0.20 mg/kg) was administered to 50 Japanese renal transplant patients every 24 h. Stepwise multiple linear regression analysis for tacrolimus dosing was performed each week to determine the effect of patient clinical characteristics. The dose-adjusted trough concentration was approximately 70% higher for patients with the CYP3A5*3/*3 than patients with the CYP3A5*1 allele before the second pre-transplantation tacrolimus dose (0.97 (0.78-1.17) vs. 0.59 (0.45-0.87) ng/mL/mg; p < 0.001). The contribution of genetic factors (CYP3A5*1 or *3) for tacrolimus dosing showed increased variation from Day 14 to Day 28 after transplantation: 7.2%, 18.4% and 19.5% on Days 14, 21 and 28, respectively. The influence of CYP3A5 polymorphisms on the tacrolimus maintenance dosage became evident after Day 14 post-transplantation, although the tacrolimus dosage was determined based only on patient body weight for the first three days after surgery. Tacrolimus dosage starting with the initial administration should be individualized using the CYP3A5 genotype information.
Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/uso terapêutico , Polimorfismo Genético , Tacrolimo/uso terapêutico , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Tacrolimo/sangue , Adulto JovemRESUMO
PURPOSE: The aim of this study was to develop a limited sampling strategy (LSS) to estimate the area under the concentration-time curve (AUC) of gefitinib using data from 18 patients with non-small-cell lung cancer. METHODS: On day 14 after beginning daily therapy with 250 mg of gefitinib, plasma samples were collected just before (C(0h), 24 hours after the 13th administration) and 1, 2, 4, 6, 8, 12, and 24 hours (C(nh)) after gefitinib administration and were analyzed by high-performance liquid chromatography. RESULTS: The predicted AUC from 0 to 24 hours (AUC0â24) from the single time point of C(12h) showed the highest correlation with the measured AUC0â24 of gefitinib (AUC0â24 = 20.0 · C(12h) + 1348.0; r² = 0.9623; P , 0.0001). The 95% confidence intervals of the slopes and intercepts of the formulae obtained by bootstrap analysis indicated acceptable accuracy and robustness in the prediction of AUC0â24 using C(0h), C(1h), C(12h), and C(1h) + C(12h). The median AUC0â24 and C(0h) of gefitinib in patients with diarrhea (n = 8) were higher than those without diarrhea (n = 10) (15,043 versus 8918 ng·h·mL⻹, respectively, P = 0.0164 and 542 versus 261 ng/mL, respectively, P = 0.0263). The area under the receiver operator curve was 0.813, giving the best sensitivity (75%) and specificity (90%) at a C(0h) threshold of 398 ng/mL. CONCLUSIONS: Use of the C(12h) single time point is recommended for the gefitinib AUC0â24 predictive equation; however, total estimation of the AUC0â24 of gefitinib at the single point of C(0h) was also precise. C(0h) monitoring of gefitinib might be beneficial during gefitinib therapy, because of a high variability in gefitinib exposure among patients taking 250 mg. Further examination of the correlation between clinical evaluation and the gefitinib exposure is necessary.
Assuntos
Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Área Sob a Curva , Carcinoma Pulmonar de Células não Pequenas/patologia , Cromatografia Líquida de Alta Pressão , Diarreia/epidemiologia , Monitoramento de Medicamentos/métodos , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Quinazolinas/uso terapêutico , Curva ROC , Sensibilidade e Especificidade , Manejo de Espécimes , Fatores de TempoRESUMO
BACKGROUND: The aim of this study was to develop a model able to predict the area under the lenalidomide plasma concentration-time curve (AUC) in multiple myeloma (MM) patients using a limited sampling strategy. METHODS: Forty-six hospitalized Japanese MM patients (25 men and 21 women) participated in this study. On days 3-10 of lenalidomide therapy, whole-blood samples were collected just before oral lenalidomide administration, and 1, 2, 4, 8, 12, and 24 hours thereafter. Plasma concentrations of lenalidomide were analyzed using liquid chromatography-tandem mass spectrometry. RESULTS: The AUC0-24 predicted from a single lenalidomide plasma concentration measured 8 hours after the administration (C8h) showed the highest correlation with the measured AUC0-24 of lenalidomide (AUC0-24 = 13.0 × C8h + 1305.0; r = 0.832). To enhance the correlation between the predicted and the actual AUC0-24 of lenalidomide, we included information regarding lenalidomide elimination by entering creatinine clearance (CCr) data in the predictive formula of lenalidomide AUC0-24. Predicting the AUC0-24 of lenalidomide using data from 2 time points, C0h and C4h, along with CCr data further strengthened the correlation with the measured AUC0-24 of lenalidomide [AUC0-24 = 37.1 × C0h + 6.4 × C4h - 32.1 × CCr + 3265.6; r = 0.842]. CONCLUSIONS: The AUC0-24 of lenalidomide can be predicted using plasma concentrations measured at only 2 time points, C0h and C4h, in combination with CCr. Our study also suggests that the limited sampling strategy approach might help to identify patients with renal function impairment and who, despite dose adjustments, accumulate the drug, leading to a high AUC.
Assuntos
Inibidores da Angiogênese/sangue , Inibidores da Angiogênese/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Inibidores da Angiogênese/farmacocinética , Área Sob a Curva , Povo Asiático , Feminino , Humanos , Lenalidomida , Masculino , Talidomida/sangue , Talidomida/farmacocinética , Talidomida/uso terapêuticoRESUMO
OBJECTIVES: We aimed to predict in vitro chemosensitivity assay results from computed tomography (CT) images by applying deep learning (DL) to optimize chemotherapy for pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: Preoperative enhanced abdominal CT images and the histoculture drug response assay (HDRA) results were collected from 33 PDAC patients undergoing surgery. Deep learning was performed using CT images of both the HDRA-positive and HDRA-negative groups. We trimmed small patches from the entire tumor area. We established various prediction labels for HDRA results with 5-fluorouracil (FU), gemcitabine (GEM), and paclitaxel (PTX). We built a predictive model using a residual convolutional neural network and used 3-fold cross-validation. RESULTS: Of the 33 patients, effective response to FU, GEM, and PTX by HDRA was observed in 19 (57.6%), 11 (33.3%), and 23 (88.5%) patients, respectively. The average accuracy and the area under the receiver operating characteristic curve (AUC) of the model for predicting the effective response to FU were 93.4% and 0.979, respectively. In the prediction of GEM, the models demonstrated high accuracy (92.8%) and AUC (0.969). Likewise, the model for predicting response to PTX had a high performance (accuracy, 95.9%; AUC, 0.979). CONCLUSIONS: Our CT patch-based DL model exhibited high predictive performance in projecting HDRA results. Our study suggests that the DL approach could possibly provide a noninvasive means for the optimization of chemotherapy.
Assuntos
Carcinoma Ductal Pancreático , Aprendizado Profundo , Neoplasias Pancreáticas , Humanos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/uso terapêutico , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Gencitabina , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/tratamento farmacológico , TomografiaRESUMO
OBJECTIVE: Axitinib is an oral multi-target tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). Because of the severe adverse events (AEs) associated with axitinib, patients often need dose reductions or discontinue its use, highlighting the need for effective biomarkers to assess efficacy and/or AEs. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in the pharmacodynamic action of axitinib and clinical prognosis and AEs in metastatic RCC (mRCC) patients. METHODS: This study included 80 mRCC patients treated with first-, second-, or third-line axitinib (5 mg orally twice daily). Clinical parameters and genetic polymorphisms were examined in 75 cases (53 males and 22 females). We assessed three SNPs in each of three candidate genes namely, angiotensin-converting enzyme (ACE), nitric oxide synthase 3 (NOS3), and angiotensin II receptor type 1 (AT1R), all of which are involved in axitinib effects on vascular endothelial function. RESULTS: Axitinib-treated patients carrying the ACE deletion allele suffered more frequently from hand-foot syndrome and a deterioration in kidney function (p = .045 and p = 0.005, respectively) whereas those carrying the NOS3 G allele suffered more frequently from proteinuria and multiple AEs (p = .025 and p = 0.036, respectively). CONCLUSIONS: Our study found that the ACE deletion allele and the NOS3 G allele are associated with increased AEs.