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Enoxaparin and daikenchuto are commonly administered to prevent venous thromboembolism and intestinal obstruction after gynecological malignancy surgery. However, the effects of their combined use on hepatic function are not well studied. This study aimed to clarify the effects of the coadministration of enoxaparin and daikenchuto on hepatic function. First, Japanese Adverse Drug Event Report (JADER) data were analyzed to identify signals of hepatic disorders. Second, a retrospective observational study of patients who underwent surgery for gynecological malignancies was conducted. This study defined hepatic disorders as an increase in aspartate aminotransferase (AST) or alanine aminotransaminase (ALT) levels above the reference values, using 1-h postoperative values as the baseline. The analysis of JADER data revealed an increased risk for hepatic disorders with the coadministration of enoxaparin and daikenchuto. An observational study also showed higher odds ratios (95% confidence intervals) for the occurrence of hepatic disorders in the coadministration group (4.27; 2.11-8.64) and enoxaparin alone group (2.48; 1.31-4.69) than in the daikenchuto alone group. The median increase in the ALT level was also higher in the coadministration group (34; 15-59) than in the enoxaparin alone (19; 6-38) and daikenchuto alone groups (8; 3-33). In conclusion, our study suggests that compared with the use of enoxaparin or daikenchuto alone, enoxaparin and daikenchuto coadministration increases the risk of hepatic disorders, with more significant increases in AST and ALT levels. Healthcare workers need to be aware of these potential side effects when combining these drugs after surgery for gynecological malignancies.
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Neoplasias de los Genitales Femeninos , Panax , Extractos Vegetales , Zanthoxylum , Zingiberaceae , Femenino , Humanos , Enoxaparina/efectos adversos , Neoplasias de los Genitales Femeninos/cirugía , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Anticoagulantes/efectos adversos , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/inducido químicamente , Complicaciones Posoperatorias/tratamiento farmacológicoRESUMEN
BACKGROUND: The clinical application of human induced pluripotent stem cell-derived cardiomyocytes (CMs) for cardiac repair commenced with the epicardial delivery of engineered cardiac tissue; however, the feasibility of the direct delivery of human induced pluripotent stem cell-derived CMs into the cardiac muscle layer, which has reportedly induced electrical integration, is unclear because of concerns about poor engraftment of CMs and posttransplant arrhythmias. Thus, in this study, we prepared purified human induced pluripotent stem cell-derived cardiac spheroids (hiPSC-CSs) and investigated whether their direct injection could regenerate infarcted nonhuman primate hearts. METHODS: We performed 2 separate experiments to explore the appropriate number of human induced pluripotent stem cell-derived CMs. In the first experiment, 10 cynomolgus monkeys were subjected to myocardial infarction 2 weeks before transplantation and were designated as recipients of hiPSC-CSs containing 2×107 CMs or the vehicle. The animals were euthanized 12 weeks after transplantation for histological analysis, and cardiac function and arrhythmia were monitored during the observational period. In the second study, we repeated the equivalent transplantation study using more CMs (6×107 CMs). RESULTS: Recipients of hiPSC-CSs containing 2×107 CMs showed limited CM grafts and transient increases in fractional shortening compared with those of the vehicle (fractional shortening at 4 weeks after transplantation [mean ± SD]: 26.2±2.1%; 19.3±1.8%; P<0.05), with a low incidence of posttransplant arrhythmia. Transplantation of increased dose of CMs resulted in significantly greater engraftment and long-term contractile benefits (fractional shortening at 12 weeks after transplantation: 22.5±1.0%; 16.6±1.1%; P<0.01, left ventricular ejection fraction at 12 weeks after transplantation: 49.0±1.4%; 36.3±2.9%; P<0.01). The incidence of posttransplant arrhythmia slightly increased in recipients of hiPSC-CSs containing 6×107 CMs. CONCLUSIONS: We demonstrated that direct injection of hiPSC-CSs restores the contractile functions of injured primate hearts with an acceptable risk of posttransplant arrhythmia. Although the mechanism for the functional benefits is not fully elucidated, these findings provide a strong rationale for conducting clinical trials using the equivalent CM products.
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Células Madre Pluripotentes Inducidas , Macaca fascicularis , Infarto del Miocardio , Miocitos Cardíacos , Esferoides Celulares , Animales , Células Madre Pluripotentes Inducidas/trasplante , Células Madre Pluripotentes Inducidas/citología , Humanos , Miocitos Cardíacos/trasplante , Infarto del Miocardio/patología , Infarto del Miocardio/terapia , Esferoides Celulares/trasplante , Regeneración , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/etiología , Arritmias Cardíacas/patología , Masculino , Trasplante de Células Madre/métodos , Modelos Animales de EnfermedadRESUMEN
BACKGROUND/OBJECTIVES: Clinical responses to naldemedine vary between individuals with advanced cancer. This is a prospective, single-center, observational study aimed to evaluate the influence of genetic polymorphisms and cachexia status on plasma naldemedine and clinical responses. METHODS: Forty-eight patients being treated with naldemedine for opioid-induced constipation under treatment of cancer pain were enrolled. Plasma naldemedine concentrations were determined on the fourth day or later after administration of naldemedine, and the associations with genotypes, cachexia status, and clinical responses were assessed. RESULTS: Cancer patients exhibited a large variation in the plasma naldemedine concentrations, and it was correlated with serum total protein level. Patients who were homozygous CYP3A5*3 had a higher plasma concentration of naldemedine than those with the *1 allele. ABCB1 genotypes tested in this study were not associated with plasma naldemedine. A negative correlation was observed between the plasma naldemedine concentration and 4ß-hydroxycholesterol level. The plasma naldemedine concentration was lower in patients with refractory cachexia than in those with precachexia and cachexia. While serum levels of interleukin-6 (IL-6) and acute-phase proteins were higher in patients with refractory cachexia, they were not associated with plasma naldemedine. A higher plasma concentration of naldemedine, CYP3A5*3/*3, and an earlier naldemedine administration after starting opioid analgesics were related to improvement of bowel movements. CONCLUSION: Plasma naldemedine increased under deficient activity of CYP3A5 in cancer patients. Cachectic patients with a higher serum IL-6 had a lower plasma naldemedine. Plasma naldemedine, related to CYP3A5 genotype, and the initiation timing of naldemedine were associated with improved bowel movements.
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Analgésicos Opioides , Caquexia , Dolor en Cáncer , Citocromo P-450 CYP3A , Naltrexona , Polimorfismo Genético , Humanos , Masculino , Femenino , Caquexia/genética , Caquexia/tratamiento farmacológico , Caquexia/etiología , Persona de Mediana Edad , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/administración & dosificación , Naltrexona/análogos & derivados , Naltrexona/farmacocinética , Naltrexona/uso terapéutico , Naltrexona/efectos adversos , Estudios Prospectivos , Anciano , Citocromo P-450 CYP3A/genética , Dolor en Cáncer/tratamiento farmacológico , Dolor en Cáncer/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/complicaciones , Genotipo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Estreñimiento Inducido por Opioides/genética , Estreñimiento Inducido por Opioides/tratamiento farmacológico , Defecación/efectos de los fármacosRESUMEN
PURPOSE: Oral aprepitant has a large interindividual variation in clinical responses in advanced cancer. This study aimed to characterize plasma aprepitant and its N-dealkylated metabolite (ND-AP) based on the cachexia status and clinical responses in head and neck cancer patients. METHODS: Fifty-three head and neck cancer patients receiving cisplatin-based chemotherapy with oral aprepitant were enrolled. Plasma concentrations of total and free aprepitant and ND-AP were determined at 24 h after a 3-day aprepitant treatment. The clinical responses to aprepitant and degrees of cachexia status were assessed using a questionnaire and Glasgow Prognostic Score (GPS). RESULTS: Serum albumin level was negatively correlated with the plasma concentrations of total and free aprepitant but not ND-AP. The serum albumin level had a negative correlation with the metabolic ratio of aprepitant. The patients with GPS 1 or 2 had higher plasma concentrations of total and free aprepitant than those with GPS 0. No difference was observed in the plasma concentration of ND-AP between the GPS classifications. The plasma interleukin-6 level was higher in patients with GPS 1 or 2 than 0. The absolute plasma concentration of free ND-AP was higher in patients without the delayed nausea, and its concentration to determine the occurrence was 18.9 ng/mL. The occurrence of delayed nausea had no relation with absolute plasma aprepitant. CONCLUSION: Cancer patients with a lower serum albumin and progressive cachectic condition had a higher plasma aprepitant level. In contrast, plasma free ND-AP but not aprepitant was related to the antiemetic efficacy of oral aprepitant.
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Antieméticos , Antineoplásicos , Neoplasias de Cabeza y Cuello , Humanos , Aprepitant , Vómitos/tratamiento farmacológico , Caquexia/tratamiento farmacológico , Caquexia/etiología , Morfolinas , Náusea/tratamiento farmacológico , Cisplatino , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Dexametasona , Antineoplásicos/efectos adversosRESUMEN
Advances in stem cell biology have facilitated cardiac regeneration, and many animal studies and several initial clinical trials have been conducted using human pluripotent stem cell-derived cardiomyocytes (PSC-CMs). Most preclinical and clinical studies have typically transplanted PSC-CMs via the following two distinct approaches: direct intramyocardial injection or epicardial delivery of engineered heart tissue. Both approaches present common disadvantages, including a mandatory thoracotomy and poor engraftment. Furthermore, a standard transplantation approach has yet to be established. In this study, we tested the feasibility of performing intracoronary administration of PSC-CMs based on a commonly used method of transplanting somatic stem cells. Six male cynomolgus monkeys underwent intracoronary administration of dispersed human PSC-CMs or PSC-CM aggregates, which are called cardiac spheroids, with multiple cell dosages. The recipient animals were sacrificed at 4 weeks post-transplantation for histological analysis. Intracoronary administration of dispersed human PSC-CMs in the cynomolgus monkeys did not lead to coronary embolism or graft survival. Although the transplanted cardiac spheroids became partially engrafted, they also induced scar formation due to cardiac ischemic injury. Cardiac engraftment and scar formation were reasonably consistent with the spheroid size or cell dosage. These findings indicate that intracoronary transplantation of PSC-CMs is an inefficient therapeutic approach.
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Miocitos Cardíacos , Células Madre Pluripotentes , Animales , Humanos , Masculino , Cicatriz/patología , Macaca fascicularis , Miocitos Cardíacos/patología , Células Madre Pluripotentes/patologíaRESUMEN
BACKGROUND: Long-term use of itraconazole (ITZ) is associated with a risk of inducing hepatotoxicity. This study aimed to evaluate the associations of plasma concentrations of ITZ and its hydroxylated metabolite (OH-ITZ) with endogenous markers of hepatic function. METHODS: Thirty six patients treated with oral ITZ solution for prophylaxis of deep mycosis were enrolled. Plasma concentrations of ITZ and OH-ITZ were determined on the 14th day or later after administration of ITZ. Their associations with endogenous marker levels of hepatic function including plasma coproporphyrin (CP)-I and OATP1B1 genotypes were assessed. RESULTS: The serum level of total bilirubin (T-Bil) was moderately correlated with the plasma concentration of total ITZ (tITZ) and OH-ITZ (tOH-ITZ). T-Bil elevation above 0.3 mg/dL was observed in 19% of patients, although statistically significant difference was not identified. The plasma concentration of tITZ had no correlation with other endogenous markers levels including AST, ALT, albumin, and plasma CP-I. The serum AST and plasma CP-I levels were correlated with the plasma concentration of free OH-ITZ (fOH-ITZ). T-Bil and plasma CP-I, a marker of OATP1B1 activity, were not correlated with each other, and neither was associated with the OATP1B1 genotypes. CONCLUSIONS: Plasma ITZ and OH-ITZ had a positive association with T-Bil. The patients with a higher fOH-ITZ level had lower OATP1B1 activity on the basis of plasma CP-I level. ITZ and OH-ITZ have the potential to slightly increase endogenous marker levels of hepatic function, although most likely by different mechanisms.
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Antifúngicos , Itraconazol , Humanos , Itraconazol/efectos adversos , Administración Oral , Antifúngicos/efectos adversosRESUMEN
PURPOSE: Plasma daptomycin has not been fully characterized in diabetic and obese patients. This study aimed to evaluate the associations of plasma daptomycin with glycation of serum albumin and obesity. METHODS: Infectious patients (n = 70) receiving intravenous daptomycin were enrolled. The plasma concentration of total and free daptomycin were determined using liquid chromatograph-tandem mass spectrometer. The associations of the plasma concentrations of daptomycin with clinical factors including serum albumin fractionations and physical status (obese including overweight, body mass index ≥ 25.0) were investigated. Daptomycin doses were adjusted using total body-weight. RESULTS: The serum albumin level was positively and negatively correlated with the plasma concentration of total daptomycin and its free fraction proportion, respectively. The serum non-glycated albumin was negatively correlated with the free fraction proportion. The dose-normalized plasma concentration of total daptomycin was higher in the obese patients than in non-obese patients when the body-weight was corrected with total and adjusted values. For the dose adjustment with lean body-weight, no difference was observed in the dose-normalized plasma concentration of total daptomycin between the physical statuses. For each body-weight correction method, physical status did not affect the dose-normalized plasma concentration of free daptomycin. CONCLUSION: The glycation of serum albumin and obesity did not associate with dose-normalized plasma free daptomycin. In obese patients, daptomycin dosage adjustment with total body-weight and adjusted body-weight may lead to an apparent excessive exposure resulting in overdosage compared to lean body-weight.
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Daptomicina , Humanos , Daptomicina/uso terapéutico , Obesidad , Albúmina Sérica , Índice de Masa CorporalRESUMEN
Objective: In the Japanese Pharmacists Act, article 25-2, revised in 2013, it states that pharmacists shall provide the necessary information and guidance to the patient based on pharmaceutical knowledge and experience for ensuring the proper use of the medicine dispensed. The package insert is one of the documents to be referred to when providing the information and guidance. The boxed warnings in package inserts that include the precautions and responses are the most significant parts, however, the suitability of boxed warnings for pharmaceutical practice has not been evaluated. The aim of this study was to investigate the boxed warning descriptions in package inserts of prescription medicines for medical professionals in Japan. Methods: Package inserts of prescription medicines listed in the Japanese National Health Insurance drug price list on March 1st 2015 were collected one by one by hand from the website of the Japanese Pharmaceuticals and Medical Devices Agency (https://www.pmda.go.jp/english/). Package inserts with boxed warnings were classified according to the Standard Commodity Classification Number of Japan based on the pharmacological activity of each medicine. They were also compiled according to their formulations. The boxed warnings were divided into the precautions and responses parts, and their characteristics were compared among medicines. (AU)
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Humanos , Prospectos de Medicamentos , Legislación Farmacéutica , Japón , MédicosRESUMEN
PURPOSE: The diuretic effect of tolvaptan is largely blood level-dependent although it does exhibit interindividual differences according to cytochrome P450 (CYP) 3A5 genotype. This study aimed to investigate the pharmacokinetic relationship between plasma tolvaptan and its monohydroxylate enantiomers and the factors affecting their metabolism in heart failure patients. METHODS: Japanese heart failure patients (n = 88) receiving oral tolvaptan (median dosage 7.5 mg/day) were enrolled. Blood samples were collected prior to the dosing on day 6 or later after first administration to determine the plasma concentrations of tolvaptan and its monohydroxylate enantiomers. Gene polymorphisms of CYP3A5, carbonyl reductase (CBR) 1/3, and ATP-binding cassette subfamily B member (ABCB) 1 were analyzed for their impact on tolvaptan pharmacokinetics. Serum laboratory test values and concomitant use of amiodarone were evaluated as factors related to tolvaptan metabolism. RESULTS: The median of the sum of the 5S- and 5R-tolvaptan plasma concentrations was 48.9 (range, 15.3-100) ng/mL. CYP3A5 genotypes significantly affected the concentration ratio of all enantiomeric metabolites to tolvaptan, while the other metabolic-related gene polymorphisms had no influence. A negative correlation was found between serum albumin and the enantiomeric ratio of tolvaptan and monohydroxylate DM-4111. Concomitant use of amiodarone increased the plasma levels of whole tolvaptan but significantly decreased the metabolic ratios of 5R-tolvaptan. 5S-tolvaptan was selectively synthesized from ketone MOP-21826 by CBR1 with a substantially smaller reaction velocity compared to tolvaptan monohydroxylation by CYP3A4/5. CONCLUSION: This study clarified the racemic impact of CYP3A5 genotypes on tolvaptan metabolism. Amiodarone may stereoselectively interact with R-forms rather than S-forms of tolvaptan.
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Amiodarona , Insuficiencia Cardíaca , Amiodarona/uso terapéutico , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Genotipo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/genética , Humanos , Inmunosupresores/farmacocinética , TolvaptánRESUMEN
PURPOSE: Serum nivolumab concentrations exhibit a large variation in cancer patients. Cancer cachexia inducing systemic inflammation promotes the elimination of endogenous proteins, while its association with serum nivolumab remains unclear. The present study aimed to evaluate the impacts of cachexia progression in addition to blood components on serum nivolumab in cancer patients. METHODS: Thirty-eight non-small-cell lung cancer or renal cell cancer patients receiving biweekly intravenous nivolumab were enrolled. Blood samples were collected just before dosing at the 7th administration of nivolumab or later. Serum nivolumab together with serum proteins, inflammatory markers, and peripheral blood leukocytes were determined. Cancer cachexia was classified using the Glasgow Prognostic Score (GPS). Immune-related adverse events (irAEs) were monitored during the study period. RESULTS: Cancer patients had a large variation in serum nivolumab concentrations (interquartile range, 12-21 µg/mL per mg/kg). The serum nivolumab concentration was positively correlated with serum albumin, while negatively associated with serum globulin and immunoglobulin G (IgG). A negative correlation was observed between serum nivolumab and blood lymphocytes. Regarding cachexia progression, the patients with GPS 2 had a higher serum interleukin-6 concentration and a lower serum nivolumab concentration than those with GPS 0 or 1. The GPS, serum IgG, and blood lymphocytes were identified as independent variables for serum nivolumab. The incidence of irAEs was not associated with the nivolumab dose or serum nivolumab. CONCLUSION: Cachexia progression had a negative impact on serum nivolumab in cancer patients. The interindividual variation in serum nivolumab was characterized by cachexia progression in addition to blood components.
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Antineoplásicos Inmunológicos/sangre , Caquexia/etiología , Caquexia/metabolismo , Neoplasias/complicaciones , Nivolumab/sangre , Anciano , Antineoplásicos Inmunológicos/farmacocinética , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Humanos , Inmunoglobulina G/metabolismo , Mediadores de Inflamación/metabolismo , Neoplasias Renales/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Nivolumab/farmacocinética , Nivolumab/uso terapéutico , Estudios RetrospectivosAsunto(s)
Sangre Fetal , Periodo Periparto , Clorhidrato de Duloxetina , Humanos , Plasma , Factores de RiesgoRESUMEN
Objective: In the Japanese Pharmacists Act, article 25-2, revised in 2013, it states that pharmacists shall provide the necessary information and guidance to the patient based on pharmaceutical knowledge and experience for ensuring the proper use of the medicine dispensed. The package insert is one of the documents to be referred to when providing the information and guidance. The boxed warnings in package inserts that include the precautions and responses are the most significant parts, however, the suitability of boxed warnings for pharmaceutical practice has not been evaluated. The aim of this study was to investigate the boxed warning descriptions in package inserts of prescription medicines for medical professionals in Japan. Methods: Package inserts of prescription medicines listed in the Japanese National Health Insurance drug price list on March 1st 2015 were collected one by one by hand from the website of the Japanese Pharmaceuticals and Medical Devices Agency (https://www.pmda.go.jp/english/). Package inserts with boxed warnings were classified according to the Standard Commodity Classification Number of Japan based on the pharmacological activity of each medicine. They were also compiled according to their formulations. The boxed warnings were divided into the precautions and responses parts, and their characteristics were compared among medicines. Results: The number of package inserts found on the website of the Pharmaceuticals and Medical Devices Agency was 15,828. Boxed warnings were present in 8.1% of the package inserts. A description of adverse drug reactions accounted for 74% of all precautions. Most of the precautions were observed in the warning boxes of antineoplastic agents. Blood and lymphatic system disorders were the most common precaution. Responses in the boxed warnings directed toward medical doctors, pharmacists, and other healthcare professionals accounted for 100, 77, and 8% of all package inserts with a boxed warning, respectively. Explanations for patients were the second most frequent response. Conclusions: The majority of boxed warnings request therapeutic contribution by pharmacists, and the descriptions of these explanations and guidance by pharmacists to patients were found to be consistent with the Pharmacists Act.
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The quantitation of serum tocilizumab using liquid chromatography tandem-mass spectrometry (LC-MS/MS) method has not been widely applied in clinical settings because of its time-consuming and costly sample pretreatments. The present study aimed to develop a validated LC-MS/MS method for detecting serum tocilizumab by utilizing immobilized trypsin without an immunoglobulin G purification step and evaluate its applicability in the treatment of rheumatoid arthritis (RA) patients administered intravenously or subcutaneously with tocilizumab. The tocilizumab-derived signature peptide was deciphered using a nano-LC system coupled to a hybrid quadrupole-orbitrap mass spectrometer. The serum tocilizumab was rapidly digested by immobilized trypsin for 30 min. The chromatographic peak of the signature peptide and that of the internal standard were separated from the serum digests for a total run time of 15 min. The calibration curve of serum tocilizumab concentration was linear with a range of 2-200 µg/mL. The intra- and inter-day accuracy and relative standard deviation (RSD) were 90.7%-109.4% and <10%, respectively. The serum tocilizumab concentrations in the RA patients receiving intravenous and subcutaneous injections were 5.8-28.9 and 2.4-63.5 µg/mL, respectively. The serum tocilizumab concentrations using the current method positively correlated with those using the enzyme-linked immunosorbent assay, although a systematic error was observed between these methods. In conclusion, a validated LC-MS/MS method with minimal sample pretreatments for monitoring serum tocilizumab concentrations in RA patients was developed.
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The quantitation of serum tocilizumab using liquid chromatography tandem-mass spectrometry(LC-MS/MS)method has not been widely applied in clinical settings because of its time-consuming and costly sample pretreatments.The present study aimed to develop a validated LC-MS/MS method for detecting serum tocilizumab by utilizing immobilized trypsin without an immunoglobulin G purification step and evaluate its applicability in the treatment of rheumatoid arthritis(RA)patients administered intrave-nously or subcutaneously with tocilizumab.The tocilizumab-derived signature peptide was deciphered using a nano-LC system coupled to a hybrid quadrupole-orbitrap mass spectrometer.The serum tocili-zumab was rapidly digested by immobilized trypsin for 30 min.The chromatographic peak of the signature peptide and that of the internal standard were separated from the serum digests for a total run time of 15 min.The calibration curve of serum tocilizumab concentration was linear with a range of 2-200 μg/mL.The intra-and inter-day accuracy and relative standard deviation(RSD)were 90.7%-109.4%and<10%,respectively.The serum tocilizumab concentrations in the RA patients receiving intravenous and subcutaneous injections were 5.8-28.9 and 2.4-63.5 pg/mL,respectively.The serum tocilizumab concentrations using the current method positively correlated with those using the enzyme-linked immunosorbent assay,although a systematic error was observed between these methods.In conclu-sion,a validated LC-MS/MS method with minimal sample pretreatments for monitoring serum tocili-zumab concentrations in RA patients was developed.
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Few studies have simultaneously investigated the impact of inflammation and genetic polymorphisms of cytochromes P450 2C19 and 3A4 on voriconazole trough concentrations. We aimed to define the respective impact of inflammation and genetic polymorphisms on voriconazole exposure by performing individual data meta-analyses. A systematic literature review was conducted using PubMed to identify studies focusing on voriconazole therapeutic drug monitoring with data of both inflammation (assessed by C-reactive protein level) and the pharmacogenomics of cytochromes P450. Individual patient data were collected and analyzed in a mixed-effect model. In total, 203 patients and 754 voriconazole trough concentrations from six studies were included. Voriconazole trough concentrations were independently influenced by age, dose, C-reactive protein level, and both cytochrome P450 2C19 and 3A4 genotype, considered individually or through a combined genetic score. An increase in the C-reactive protein of 10, 50, or 100 mg/L was associated with an increased voriconazole trough concentration of 6, 35, or 82%, respectively. The inhibitory effect of inflammation appeared to be less important for patients with loss-of-function polymorphisms for cytochrome P450 2C19. Voriconazole exposure is influenced by age, inflammatory status, and the genotypes of both cytochromes P450 2C19 and 3A4, suggesting that all these determinants need to be considered in approaches of personalization of voriconazole treatment.
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PURPOSE: Cetuximab inhibits epidermal growth factor receptor (EGFR) signaling in cancer and skin cells, thereby inducing anti-cancer effects and skin disorders. The present study aimed to evaluate the relationships between serum cetuximab and EGFR-related markers, and adverse effects in head and neck cancer patients. METHODS: Thirty-four head and neck cancer patients receiving weekly intravenous cetuximab were enrolled. Serum cetuximab levels were determined just before dosing. Blood samples for determination of serum EGFR-related markers including soluble epidermal growth factor receptor (sEGFR) and interleukin-6 (IL-6) were obtained. The severities of skin disorders, their medications, and hypomagnesemia treatment were also assessed. RESULTS: Serum levels of cetuximab and sEGFR were negatively and positively correlated with that of IL-6, respectively. The serum cetuximab level was twofold higher in the patients with a grade 2-3 skin rash than with a grade 0-1 rash. The serum cetuximab cutoff value related to severe skin rash was 71 µg/mL (sensitivity, 59%; and specificity, 94%). The use of a strong topical corticosteroid for skin rash was also associated with a higher serum cetuximab level. Serum levels of sEGFR and IL-6 had no correlations with the skin disorder severities or their medications. Hypomagnesemia treatment using intravenous magnesium sulfate was not related to serum cetuximab and EGFR-related markers. CONCLUSIONS: Head and neck cancer patients with a higher serum IL-6 level tended to have a lower serum cetuximab level. Serum cetuximab had positive correlations to skin rash severity and its medication in the study population.
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Cetuximab/sangre , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Enfermedades de la Piel/inducido químicamente , Anciano , Cetuximab/efectos adversos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/sangre , Femenino , Neoplasias de Cabeza y Cuello/sangre , Humanos , Interleucina-6/sangre , Magnesio/sangre , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: Aprepitant, an antiemetic selective neurokinin-1 receptor antagonist, is primarily metabolized to the active N-dealkylated form (ND-AP) and then converted to its carbonyl form (ND-CAP) in humans. This study developed a simple liquid chromatography-tandem mass spectrometry method using electrospray ionization for the quantitation of plasma total and free aprepitant and its N-dealkylated metabolites and used them to analyze patient plasma. METHODS: Free aprepitant and ND-AP in plasma were fractionated using centrifugal ultrafiltration. The analytes in plasma or their ultrafiltered specimens treated with triethylamine/acetonitrile were isocratically separated using a 3-µm octadecylsilyl column with a total run time of 10 minutes and scanned using positive ion electrospray ionization. RESULTS: The calibration curves of total aprepitant, ND-AP, and ND-CAP were prepared at concentration ranges of 50-2500, 20-1000, and 5-250 ng/mL, respectively, whereas that of free aprepitant and ND-AP were at a concentration range of 2-150 ng/mL. The intraassay and interassay accuracy and imprecision values were 93.5%-107.7% and 94.6%-103.3%, and 2.1%-7.5% and 1.0%-8.9%, respectively. Aprepitant and its metabolites did not exhibit any matrix effects or instabilities in the plasma specimens. In cancer patients receiving oral aprepitant, the plasma concentration ranges of total aprepitant, ND-AP, and ND-CAP, and free aprepitant and ND-AP were 137-2170, 104-928, 22.4-97.6, 8.11-60.0, and 3.53-56.0 ng/mL, respectively. The median plasma free fraction proportion of aprepitant and ND-AP was 4.14% and 4.90%, respectively. CONCLUSIONS: The present developed method showed an acceptable analytical performance and can be used to evaluate total and free aprepitant and its N-dealkylated metabolites in patient plasma.
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Aprepitant/farmacocinética , Cromatografía Liquida , Espectrometría de Masas en Tándem , Aprepitant/sangre , Calibración , Humanos , Plasma , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
PURPOSE: Serum markers of renal function have not been characterized in patients treated with itraconazole (ITZ). This study aimed to evaluate the associations between plasma ITZ and its hydroxylated metabolite (OH-ITZ) concentrations and serum markers of renal function in patients with hematopoietic or immune-related disorder. METHODS: This study enrolled 40 patients with hematopoietic or immune-related disorder who are receiving oral ITZ solution. Plasma concentrations of ITZ and OH-ITZ at 12 h after dosing were determined at steady state. Their relationships with serum levels of creatinine and cystatin C and their estimated glomerular filtration rate (eGFR) were evaluated. RESULTS: The free plasma concentration of ITZ had no correlation with serum creatinine and serum creatinine-based estimated glomerular filtration rate (eGFR-cre). The free plasma concentration of OH-ITZ was positively and negatively correlated with serum creatinine and eGFR-cre, respectively. The free plasma concentrations of ITZ and OH-ITZ had no association with serum cystatin C and serum cystatin C-based eGFR. Serum creatinine was higher by 16% after than before starting ITZ treatment, while eGFR-cre was lower by 9.3%. The serum creatinine ratio after/before ITZ treatment was positively correlated with the free plasma concentration of OH-ITZ. The patients co-treated with trimethoprim-sulfamethoxazole had higher serum creatinine. Concomitant glucocorticoid administration did not significantly alter serum cystatin C. CONCLUSIONS: Patients with hematopoietic or immune-related disorder treated with oral ITZ had a higher level of serum creatinine. Although serum creatinine potentially increases in conjunction with the free plasma concentration of OH-ITZ, concomitant ITZ administration has a slight impact on the eGFR-cre level in clinical settings.
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Antifúngicos/farmacocinética , Enfermedades Hematológicas/tratamiento farmacológico , Enfermedades del Sistema Inmune/tratamiento farmacológico , Itraconazol/farmacocinética , Administración Oral , Anciano , Antifúngicos/administración & dosificación , Creatinina/sangre , Cistatina C/sangre , Femenino , Tasa de Filtración Glomerular , Humanos , Hidroxilación , Itraconazol/administración & dosificación , Masculino , Persona de Mediana EdadRESUMEN
This study aimed to evaluate the influence of CYP2D6 activity and cachexia progression on the enantiomeric alteration of plasma tramadol and its demethylated metabolites in head and neck cancer patients. Fifty-three head and neck cancer patients receiving oral tramadol were enrolled. The plasma concentrations of tramadol, O-desmethyltramadol (ODT) and N-desmethyltramadol (NDT) enantiomers were determined. The CYP2D6 activity score (AS) and degree of cachexia progression were assessed according to genotype and the Glasgow Prognostic Score (GPS), respectively. The enantiomeric ratio of NDT was (+)-form dominant in all patients. CYP2D6 AS had negative correlations with the plasma concentrations of (+)-NDT and (-)-NDT. The plasma concentrations of (+)-tramadol and (+)-ODT were higher in patients with GPS 1 or 2 than in those with GPS 0. Lower metabolic ratios to NDT enantiomers were observed in patients with GPS 1 or 2. In patients with GPS 1 or 2, the plasma (-)-tramadol was associated with the incidence of central nervous system symptoms. In conclusion, CYP2D6 AS partially explained the contribution of CYP2D6 activity to plasma tramadol and its demethylated metabolite enantiomers. Additionally, cachexia progression elevated the plasma (+)-tramadol and (+)-ODT levels through the reduction of N-demethylation of (+)-tramadol.