RESUMO
Mycophenolate mofetil (MpM) is a medication used to prevent the rejection of transplanted organs, particularly in kidney, heart, and liver transplant surgeries. It is extremely important to be conscious that MpM can raise the risk of severe infections and some cancers if it exceeds the recommended dose while lower doses will result in organ rejections. So, it is essential to monitor the dosage of MpM in real time in the micromolar range. In this work, we have synthesized 3-aminopropyltriethoxysilane (APTES) functionalized nickel cobaltite (NiCo2O4) and this amino functionalization was chosen to enhance the stability and electrochemical activity of NiCo2O4. The enhanced activity of NiCo2O4 was used for developing an electrochemical sensor for the detection of MpM. APTES functionalized NiCo2O4 was coated on carbon cloth and used as the working electrode. Surface functionalization with APTES on NiCo2O4 was aimed at augmenting the adsorption/interaction of MpM due to its binding properties. The developed sensor showed a very low detection limit of 1.23 nM with linear ranges of 10-100 nM and 1-100 µM and its practical applicability was examined using artificial samples of blood serum and cerebrospinal fluid, validating its potential application in real-life scenarios.
Assuntos
Carbono , Imunossupressores , Limite de Detecção , Ácido Micofenólico , Nanoestruturas , Níquel , Ouriços-do-Mar , Dispositivos Eletrônicos Vestíveis , Animais , Níquel/química , Ácido Micofenólico/sangue , Ácido Micofenólico/química , Ácido Micofenólico/análise , Imunossupressores/sangue , Imunossupressores/análise , Imunossupressores/química , Carbono/química , Ouriços-do-Mar/química , Nanoestruturas/química , Técnicas Eletroquímicas/métodos , Técnicas Eletroquímicas/instrumentação , Propilaminas/química , Humanos , Cobalto/química , Eletrodos , SilanosRESUMO
Additional immunomodulatory treatment is needed for the management of immune-mediated disease in horses. Mycophenolate mofetil (MMF) is an immunomodulatory agent used in human and veterinary medicine for the prevention of graft rejection and the management of autoimmune diseases. Few studies exist investigating the pharmacokinetics of MMF in horses. The aim of this study was to evaluate the pharmacokinetics of a single dose of MMF in healthy horses in the fed vs. fasted state. Six healthy Standardbred mares were administered MMF 10 mg/kg by a nasogastric (NG) tube in a fed and fasted state. A six-day washout period was performed between the two doses. No statistically significant differences in mycophenolic acid (MPA) concentrations were seen at any time point apart from 8 h, when plasma metabolite concentrations were significantly higher in the fasted state compared to the fed state (p = .038). Evidence of enterohepatic recirculation was seen only in the fasted state; this did not yield clinical differences in horses administered a single-dose administration but may be significant in horses receiving long-term MMF treatment.
Assuntos
Imunossupressores , Ácido Micofenólico , Animais , Cavalos/metabolismo , Cavalos/sangue , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/sangue , Feminino , Imunossupressores/farmacocinética , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Interações Alimento-Droga , Área Sob a Curva , Meia-Vida , Estudos Cross-OverRESUMO
The aim of the work was to prepare a simple but reliable HPLC-UV method for the routine monitoring of mycophenolic acid (MPA). Sample preparation was based on plasma protein precipitation with acetonitrile. The isocratic separation of MPA and internal standard (IS) fenbufen was made on Supelcosil LC-CN column (150 × 4.6 mm, 5 µm) using a mobile phase: CH3CN:H2O:0.5M KH2PO4:H3PO4 (260:700:40:0.4, v/v). UV detection was set at 305 nm. The calibration covered the MPA concentration range: 0.1-40 µg/mL. The precision was satisfactory with RSD of 0.97-7.06% for intra-assay and of 1.92-5.15% for inter-assay. The inaccuracy was found between -5.72% and +2.96% (+15.40% at LLOQ) and between -8.82% and +5.31% (+19.00% at LLOQ) for intra- and inter-assay, respectively, fulfilling acceptance criteria. After a two-year period of successful application, the presented method has been retrospectively calibrated using the raw data disregarding the IS in the calculations. The validation and stability parameters were similar for both calculation methods. MPA concentrations were recalculated and compared in 1187 consecutive routine therapeutic drug monitoring (TDM) trough plasma samples from mycophenolate-treated patients. A high agreement (r2 = 0.9931, p < 0.0001) of the results was found. A Bland-Altman test revealed a mean bias of -0.011 µg/mL (95% CI: -0.017; -0.005) comprising -0.14% (95% Cl: -0.39; +0.11), whereas the Passing-Bablok regression was y = 0.986x + 0.014. The presented method can be recommended as an attractive analytical tool for medical (hospital) laboratories equipped with solely basic HPLC apparatus. The procedure can be further simplified by disapplying an internal standard while maintaining appropriate precision and accuracy of measurements.
Assuntos
Cromatografia Líquida de Alta Pressão/normas , Ácido Micofenólico/sangue , Calibragem , Humanos , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
INTRODUCTION: Little is known about the relationship between exposure levels of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and comorbidities of systemic lupus erythematosus (SLE) in children. This study aims to explore this association. METHODS: Longitudinal data from SLE children, who were taking MMF for immunosuppression and under therapeutic drug monitoring (TDM), were retrospectively collected. Area under the concentration-time curve of mycophenolic acid (MPA) over 24 hours (AUC0-24h) was estimated with Bayesian methods. Logistic regression and random forest models were used to explore the association between comorbidities and MPA exposure levels. RESULTS: This study included 107 children with 358 times of follow-up (median age 169.02 months). The incidence of diabetes, acute kidney injury (AKI), or pneumonia was significantly associated with AUC0-24h (odds ratio [OR] 0.991, 95% confidence interval [CI] 0.982-0.999), SLE duration (OR 1.012, 95% CI 1.002-1.022), lymphocyte percentage (OR 0.959, 95% CI 0.925-0.991), plasma albumin levels (OR 0.891, 95% CI 0.843-0.940), use of aspirin (OR 0.292, 95% CI 0.126-0.633) and hydroxychloroquine (OR 0.407, 95% CI 0.184-0.906). The random forest model showed that albumin and AUC0-24h were two important predictors. The case group (with the three comorbidities) had a mean AUC0-24h of 73.63 mg · h/L, while the control group had a mean AUC0-24h of 100.39 mg · h/L. CONCLUSIONS: Increased levels of MPA exposure are associated with decreased incidence odds of diabetes, AKI or pneumonia in SLE children. An AUC0-24h of 100.39 mg · h/L or an AUC0-12h of 50.20 mg · h/L could be used as the targeted exposure level for clinical practice.
Assuntos
Monitoramento de Medicamentos , Imunossupressores , Lúpus Eritematoso Sistêmico , Ácido Micofenólico , Adolescente , Área Sob a Curva , Teorema de Bayes , Criança , Pré-Escolar , Comorbidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/sangue , Ácido Micofenólico/uso terapêutico , Estudos RetrospectivosRESUMO
Extracorporeal blood purification is considered an adjunct therapy in critically ill patients with life-threatening conditions such as sepsis and septic shock. It consists of cytokine removal, removal of endotoxins, a combination of both, or the removal of pathogens themselves. The latter technique was introduced for clinical application very recently. This case study describes a case of a 69-year-old female lung transplant recipient patient with a persistent VV-ECMO-related septic deep vein thrombosis with continuous renal replacement therapy-dependent acute kidney injury initiated on the Seraph®-100 Microbind Affinity Filter in order to control the persistent bacteraemia with coagulase-negative staphylococci. Drug plasma concentrations (vancomycin, tacrolimus, and mycophenolic acid) were measured before and after the device to calculate absorber-related drug clearance.
Assuntos
Antibacterianos/sangue , Hemoperfusão/instrumentação , Imunossupressores/sangue , Ácido Micofenólico/sangue , Tacrolimo/sangue , Vancomicina/sangue , Idoso , Antibacterianos/isolamento & purificação , Feminino , Filtração/instrumentação , Humanos , Imunossupressores/isolamento & purificação , Ácido Micofenólico/isolamento & purificação , Tacrolimo/isolamento & purificação , Vancomicina/isolamento & purificaçãoRESUMO
BACKGROUND: Graft acceptance against immunity is one of the major challenges in solid organ transplant. Immunosuppressive medications have effectively improved the post-transplantation outcome however, it has its own limitations. Genetic polymorphisms in drug-metabolizing enzymes have been identified as the potential targets in developing a pharmacogenetic strategy, to individualize drug dose and also in preventing the adverse events. OBJECTIVE: The rationale of the study was to explore polymorphisms in tacrolimus and mycophenolate metabolic pathways that influence the adverse clinical outcomes in renal transplant recipients. METHODS: A total of 255 renal transplant recipients were analyzed for the pharmacogenetic determinants of tacrolimus (CYP3A5*3 ABCB1 1236 T>C ABCB1 2677 G>A/T ABCB1 3435 T>C) and mycophenolate (UGT1A8*3 UGT1A9 IMPDH I IMPDH II c.787C>T ABCC2 -24 C>T and c.3972C>T) using Sanger sequencing. RESULTS: Acute rejection (AR) was observed in 5.88% of the transplant recipients whereas acute tubular necrosis (ATNs) was observed in 7.45% of the patients within early stage of the maintenance phase. Infections such as urinary tract infection (UTI) and cytomegalovirus (CMV) infection were observed in 11.37% and 12.16% of the patients. The AUC of mycophenolate was significantly higher in patients with increased risk for infections. ABCC2 -24 C>T c.3972C>T polymorphisms and ABCB1 3435 C-allele were associated with reduced risk for infections. ABCC2 rs3740066 was associated with 2.06-fold all-cause mortality risk. CYP3A5 AG- and UGT1A9-440 CC-genotypes showed increased risk and ABCC 3972C>T CC-genotype showed protection against adverse events. CONCLUSION: Genetic variants in tacrolimus and mycophenolate metabolic pathways were found to influence the morbidity and mortality in renal transplant recipients.
Assuntos
Imunossupressores/administração & dosagem , Transplante de Rim/efeitos adversos , Ácido Micofenólico/administração & dosagem , Polimorfismo Genético/efeitos dos fármacos , Tacrolimo/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adulto , Citocromo P-450 CYP3A/genética , Feminino , Humanos , IMP Desidrogenase/genética , Imunossupressores/sangue , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla/genética , Ácido Micofenólico/sangue , Ácido Micofenólico/farmacologia , Farmacogenética , Tacrolimo/sangue , Tacrolimo/farmacologia , UDP-Glucuronosiltransferase 1A/genéticaRESUMO
A simple and sensitive LC-MS/MS method was established to quantify total and free mycophenolic acid (MPA) plasma concentrations during immunosuppressive medication for pediatric renal transplantation. The chromatographic separation was performed with the Hypersil GOLD C18 column, using a mobile phase consisting of 0.1% formic acid in water and acetonitrile (60:40, v/v) at an isocratic flow rate of 0.4 ml/min. An Agilent 6420 triple quadrupole mass spectrometer was operated via a positive electrospray ionization interface using the transitions m/z 321.14 â 206.9 for MPA and m/z 324.15 â 209.9 for MPA-d3 (internal standard). The linearity was 0.1-50 µg/ml for total MPA and 0.0025-0.5 µg/ml for free MPA. The within-run and between-run precisions were all <5% and accuracy was within 96.23-107.63%. The validated method was successfully aspplied to a pharmacokinetic study in 28 pediatric renal recipients. The mean free fraction of MPA in our patients was 0.89% (ranging from 0.62 to 1.25%) and albumin level played a major role in the variability of free fraction of MPA, thus, in pediatric patients with hypoproteinemia, close free drug monitoring and dose adjustments should be considered to prevent toxicity.
Assuntos
Cromatografia Líquida/métodos , Imunossupressores/sangue , Ácido Micofenólico/sangue , Espectrometria de Massas em Tandem/métodos , Adolescente , Criança , Pré-Escolar , Monitoramento de Medicamentos , Feminino , Humanos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Transplante de Rim , Modelos Lineares , Masculino , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
WHAT IS KNOWN AND OBJECTIVE: The removal rates of tacrolimus (TAC) and mycophenolic acid (MPA) by simultaneous plasma exchange (PE) and continuous hemodiafiltration (CHDF) are not clear. CASE SUMMARY: We evaluated the removal rates of TAC and MPA by PE and CHDF started simultaneously 5 hours after administration in a lung transplant patient. TAC was not removed. MPA was transferred into the PE effluent, but the total amount in the effluent was only 1% of the dosage. WHAT IS NEW AND CONCLUSION: TAC and MPA were less likely to be removed by PE and CHDF initiated 5 hours after administration.
Assuntos
Hemodiafiltração/métodos , Imunossupressores/sangue , Ácido Micofenólico/sangue , Troca Plasmática/métodos , Tacrolimo/sangue , Adulto , Feminino , Humanos , Transplante de Pulmão/métodos , Ligação ProteicaRESUMO
This study presents, for the first time, the development and validation of a liquid chromatography and time-of-flight mass-spectrometry (LC-TOF-MS) based assay to quantify mycophenolic acid (MPA) in patient samples as part of a routine therapeutic drug monitoring service. MPA was extracted from 50 µl human plasma by protein precipitation, using sulindac as internal standard (IS). Separation was obtained on a Luna™ Omega polar C18 column kept at 40°C. The mobile phase consisted of a mixture of acetonitrile-deionized water (50:50, v/v) with 0.1% formic acid at a flow rate of 350 µl/min. Analyte and IS were monitored on a TOF-MS using a Jet-Stream™ (electrospray) interface running in positive mode. Assay performance was evaluated by analysing patient plasma (N = 69) and external quality assessment (N = 6) samples. The retention times were 2.66 and 2.18 min for MPA and IS, respectively. The lower limit of quantification of MPA was 0.1 µg/ml. The within- and between-assay reproducibility results ranged from 1.81 to 10.72%. Patient and external quality assessment sample results were comparable with those obtained previously by an in-house validated LC-MS/MS method. This method showed satisfactory analytical performance for the determination of MPA in plasma over the calibration range of 0.1-15.0 µg/ml.
Assuntos
Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Imunossupressores/sangue , Ácido Micofenólico/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Humanos , Imunossupressores/química , Imunossupressores/farmacocinética , Modelos Lineares , Ácido Micofenólico/química , Ácido Micofenólico/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND AND OBJECTIVE: Mycophenolate mofetil is widely used in kidney transplant recipients. Mycophenolate mofetil is hydrolysed by blood esterases to mycophenolic acid (MPA), the active drug. Although MPA therapeutic drug monitoring has been recommended to optimise the treatment efficacy by the area under the plasma concentration vs time curve, little is known regarding MPA concentrations in peripheral blood mononuclear cells, where MPA inhibits inosine monophosphate dehydrogenase. This study aimed to build a pharmacokinetic model using a population approach to describe MPA total and unbound concentrations in plasma and into peripheral blood mononuclear cells in 78 adult kidney transplant recipients receiving mycophenolate mofetil therapy combined with tacrolimus and prednisone. METHODS: Total and unbound plasma concentrations and peripheral blood mononuclear cell concentrations were assayed. A three-compartment model, two for plasma MPA and one for peripheral blood mononuclear cell MPA, with a zero-order absorption and a first-order elimination was used to describe the data. RESULTS: Mycophenolic acid average concentrations in peripheral blood mononuclear cells were well above half-maximal effective concentration for inosine monophosphate dehydrogenase and no relationship was found with the occurrence of graft rejection. Three covariates affected unbound and intracellular MPA pharmacokinetics: creatinine clearance, which has an effect on unbound MPA clearance, human serum albumin, which influences fraction unbound MPA and the ABCB1 3435 C>T (rs1045642) genetic polymorphism, which has an effect on MPA efflux transport from peripheral blood mononuclear cells. CONCLUSION: This population pharmacokinetic model demonstrated the intracellular accumulation of MPA, the efflux of MPA out of the cells being dependent on P-glycoprotein transporters. Nevertheless, further studies are warranted to investigate the relevance of MPA concentrations in peripheral blood mononuclear cells to dosing regimen optimisation.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/farmacocinética , Leucócitos Mononucleares/química , Ácido Micofenólico/farmacocinética , Pró-Fármacos/farmacocinética , Adulto , Idoso , Estudos Clínicos como Assunto , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Rejeição de Enxerto/metabolismo , Humanos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Transplante de Rim , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Ácido Micofenólico/sangue , Ácido Micofenólico/uso terapêutico , Pró-Fármacos/uso terapêutico , Albumina Sérica/análise , Adulto JovemRESUMO
BACKGROUND: Monitoring immunosuppressant levels, such as mycophenolic acid (MPA), cyclosporin A (CsA), and tacrolimus (TAC), in peripheral blood mononuclear cells (PBMCs) could be useful in organ transplant patients administered individualized therapy. The authors developed a liquid chromatography-tandem mass spectrometry assay technique to simultaneously determine immunosuppressant levels in PBMCs and assess their pharmacokinetics in Chinese renal allograft recipients. METHODS: PBMCs were isolated from the whole blood of 27 Chinese renal transplant patients using Ficoll-Paque Plus solution, and cell number was determined; acetonitrile treatment for protein precipitation, and gradient elution was performed on an Agilent Eclipse XDB-C18 column (3.5 µm, 2.1 × 100 mm) with mobile phase: water and methanol (containing 2 mM ammonium formate); flow rate: 0.3 mL·min. RESULTS: The calibration curves of MPA, CsA, and TAC had a linear range (ng·mL): 0.098-39.2 (r = 0.9987), 0.255-102 (r = 0.9969), and 0.028-11.2 (r = 0.9993), respectively. The extraction effects, matrix effects, and mean relative recovery of these immunosuppressants were 70.4%-93.2%, 72.7%-96.5%, and 90.1%-112.4%, respectively. The within-day and between-day coefficients of variation were <15%. The AUC0-12 of MPA in PBMCs correlated well with those in plasma. The level of MPA, CsA, and TAC in PBMCs might be more stable during dosing interval. CONCLUSIONS: The derived liquid chromatography-tandem mass spectrometry assay is suitable for simultaneously monitoring different immunosuppressants in PBMCs. Pharmacokinetic of MPA, CsA, and TAC displayed considerable interindividual variability. Intracellular monitoring of immunosuppressants may facilitate individualized therapy for renal allograft recipients.
Assuntos
Cromatografia Líquida/métodos , Imunossupressores/sangue , Imunossupressores/farmacocinética , Leucócitos Mononucleares/química , Espectrometria de Massas em Tandem/métodos , Adolescente , Povo Asiático , Ciclosporina/sangue , Ciclosporina/farmacocinética , Ciclosporina/uso terapêutico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Imunossupressores/uso terapêutico , Rim/metabolismo , Transplante de Rim/métodos , Masculino , Ácido Micofenólico/sangue , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapêutico , Tacrolimo/sangue , Tacrolimo/farmacocinética , Tacrolimo/uso terapêutico , TransplantadosRESUMO
BACKGROUND: Tacrolimus and mycophenolic acid (MPA) are the most important immunosuppressive drugs in modern heart transplantation. The pharmacokinetics of tacrolimus are best described by a 2-compartment model. MPA has very variable pharmacokinetics. The aim of this research was to compare kinetics of the immunosuppressants' blood levels in a group of patients with and without graft rejection. MATERIALS AND METHODS: The study was a retrospective analysis of 39 consecutive adult orthotopic heart transplantations (OHT): 10 (9 men and 1 woman) in group R had graft rejection (ISHLT >2) in the first biopsy and 29 (22 men and 7 women) in group C were without rejection. Ischemic cardiomyopathy occurred in 2 of 7 and nonischemic cardiomyopathy in 8 of 22 (group R and group C, respectively). RESULTS: Patients did not differ between groups except diabetes, which occurred more often in group R. Immunosuppressive drug levels were: group R and group C, respectively, 2.13 ± 0.49 and 2.11 ± 0.72 µg/mL; P = .93 for mycophenolate mofetil (MMF) and 9.42 ± 1.76 and 9.63 ± 2.30 ng/mL; P = .75 for tacrolimus. ICU stay was 14 ± 11 vs 15 ± 15 days; P = .76. There were 2 of 6 primary graft failures, 1 of 1 neurologic complications, and 0 of 6 reoperations (P < .05) in group R and group C, respectively. One patient died from group C in 30 days. During the hospital stay the incidence of graft rejection was diagnosed in 20 patients (16men and 4 women) (ISHLT >2 in endomyocardial biopsy) in the study population. CONCLUSIONS: Monitoring of tacrolimus concentration in the early post--heart transplant period does not identify patients with rejection in the authors' study. Monitoring concentration of MMF does not identify patients with rejection. Further investigation is needed to evaluate factors responsible for post--heart transplant rejection in the early phase.
Assuntos
Rejeição de Enxerto/epidemiologia , Transplante de Coração/efeitos adversos , Imunossupressores/sangue , Ácido Micofenólico/sangue , Tacrolimo/sangue , Adulto , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/farmacocinética , Incidência , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/farmacocinética , Estudos Retrospectivos , Tacrolimo/farmacocinéticaRESUMO
OBJECTIVES: Mycophenolate mofetil (MMF) is mainly used in conjunction with calcineurin inhibitors as an additional immunosuppressive for renal sparing after liver transplantation. However, few reports about MMF use in infants after living donor liver transplantation (LDLT) are available. The purpose of this study was to examine the efficacy and safety of MMF in infants. METHODS: This study enrolled infants younger than 1 year of age who received LDLT at our institution. Patients received oral MMF twice daily. The initial dose was 40 to 50 mg/kg/d, which was increased to a target mycophenolic acid (MPA) trough level of 2 mg/L. Body weight, height, MMF dose, MPA trough level, acute cellular rejection (ACR) episodes, pathologic findings, and adverse effects were analyzed. Allograft fibrosis was graded using the Meta-analysis of Histological Data in Viral Hepatitis score. RESULTS: Patients received MMF for refractory ACR (n = 2), fulminant hepatitis (n = 2), and pre-existing antibodies (n = 1). Original diseases were biliary atresia (n = 3) and fulminant hepatitis (n = 2). Mean age at transplant was 8 months (range 3-10 months). The last available mean trough level was 2.7 mg/L. The mean dose was 66 mg/kg/d or 1429 mg/m2/d at the time of the last available through level. The regression line for MMF dose and MPA trough level was y = 1.8 × 10-3x. The correlation coefficient was 0.65. All allografts showed F1 to F2 fibrosis. Two patients discontinued MMF because of infection and bone marrow suppression, respectively. Two patients converted to everolimus. One patient continued on MMF. CONCLUSIONS: After LDLT, infants require a higher MMF dose than older patients based on trough levels, but allograft fibrosis can progress.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/administração & dosagem , Transplante de Fígado , Ácido Micofenólico/administração & dosagem , Feminino , Humanos , Imunossupressores/sangue , Lactente , Doadores Vivos , Masculino , Ácido Micofenólico/sangue , Fatores de TempoRESUMO
Mycophenolate mofetil (MMF) is typically used in combination with prednisone and tacrolimus to avoid graft rejection in kidney transplant patients. The aim of this study was to develop and validate a population pharmacokinetic model of mycophenolic acid (MPA) in kidney transplant patients to investigate the influence of clinical and genetic covariates and to propose a dosage regimen based on the final model. Adult kidney transplant patients (>18 years old) receiving combination of MMF, prednisone and tacrolimus regimen were included. The population pharmacokinetic model was built using a two-compartment model and First Order Conditional Estimation method with Interaction (FOCEI though NONMEM v.7.4.). A total of 343 MPA concentrations at steady state from 77 kidney transplant patients were included in the analysis. MPA CL/F, V1/F, Q/F, V2/F, and Ka were 12.4 L/h, 45.6 L, 29.9 L/h, 658 L, and 1.67 h-1, respectively. It was found that CL/F increases with serum creatinine and uric acid levels and V1/F is modified by blood urea nitrogen and the UGT1A9 genotype. In the final model the interindividual variabilities associated to CL/F and V1/F were 56.5% and 105.8%, respectively. The residual variability was 41.8%. Evaluation by bootstrapping showed that the final model was stable. The predictive performance was evaluated by goodness-of-fit plots and visual predictive check. Dosage regimens for MMF were proposed based on the final model and would be appropriate for a prospective evaluation. In conclusion, it was built a population pharmacokinetic model for MPA in kidney transplant patients, which include clinical and genetic covariates.
Assuntos
Imunossupressores/farmacocinética , Transplante de Rim , Modelos Biológicos , Ácido Micofenólico/farmacocinética , Adolescente , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Glucuronosiltransferase/genética , Humanos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/sangue , Ácido Micofenólico/uso terapêutico , Prednisona/uso terapêutico , Tacrolimo/uso terapêutico , UDP-Glucuronosiltransferase 1A , Ácido Úrico/sangue , Adulto JovemRESUMO
BACKGROUND: Therapeutic drug monitoring (TDM) of the immunosuppressant mycophenolic acid (MPA) is especially recommended for the control of personalized immunosuppressive therapy. Various test systems are available for MPA monitoring, including high performance liquid chromatography combined with UV detection (HPLC-UV) and isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS). METHODS: In the present work, commercially available kits for MPA monitoring with HPLC-UV and ID-LC-MS/ MS were subjected to routine use TDM. Following method verification according to the Clinical and Laboratory Standards Institute (CLSI) guidelines, 105 native sample duplicates from patients under therapy with mycophenolate mofetil were assayed with both procedures for comparative testing. RESULTS: Using bi-level quality controls, the estimate of repeatability, within-laboratory imprecision and inaccuracy were ≤ 5.18%, ≤ 5.95% and ≤ 3.86% for all MPA measurements. Weighted Deming regression analysis yielded a slope of 0.93, an intercept of 0.04, and Pearson's correlation coefficient (r) of 0.99, while Bland-Altman analysis showed a combined relative bias of 4.93% (± 1.96 SD: -16.68 - 26.54%). Plasma samples taken from a patient re-peatedly showed the presence of an interferent only in HPLC-UV analysis. CONCLUSIONS: Based on these results, HPLC-UV testing can be considered suitable for routine TDM of MPA in the clinical setting with high precision. Due to the risk of unforeseen analytical interference in ever-increasing multimorbidity and polypharmacy, highly selective ID-LC-MS/MS methodology should be given preference over HPLC-UV analysis whenever feasible.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Ácido Micofenólico/sangue , Espectrofotometria Ultravioleta/métodos , Espectrometria de Massas em Tandem/métodos , Humanos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Radioisótopos/metabolismo , Reprodutibilidade dos TestesRESUMO
BACKGROUND Antiproliferative drugs including mycophenolate mofetil (MMF) are widely accepted part of an immunosuppressive therapy following heart transplantation. Proton pump inhibitors (PPIs) are routinely administered after cardiac surgery procedures including transplantation. They may also have impact on mycophenolate acid (MPA) serum levels. MATERIAL AND METHODS There were 30 consecutive patients (28 male and 2 female patients) with a mean age of 45±12 years who were enrolled into this study. MPA serum levels were studied; PPIs were intravenously and orally administered. RESULTS The mean MPA plasma concentrations were statistically significantly different between parenteral group (2.3±1.4 umg/mL) and oral group (3.1±2.2 umg/mL) (P=0.036) before immunosuppressive drug administration (C-0 time). There was a statistically significant different drug concentration at the second sample time C-30 (30 minutes after drug intake) reaching 4.4±2.8 umg/mL versus 7.9±4.5 umg/mL (P<0.05). There was no statistically significant difference in MPA plasma concentration at the 3rd measurement C-120 (10.7±4,9 umg/mL versus 9.8±5 umg/mL) (P=0.3). There is a statistically significant different MMF serum concentration after oral intake and intravenous infusion at C-30 (2.4±1.4 in group 1 versus 3.3±2.5 in group 2, P<0.036) but not at C-120 time interval (8.9±5.0 versus 9.8±5.3 in group 1 and 2, respectively) (P=0.3). CONCLUSIONS Our study was the first study that compared different routes of PPI co-administration on MPA serum levels in a transplant recipient group. Our study revealed that the parenteral route of administration only slowed not decreased MPA pharmacokinetics within 120 minutes following MMF administration.
Assuntos
Transplante de Coração/métodos , Imunossupressores/farmacocinética , Ácido Micofenólico/sangue , Ácido Micofenólico/farmacocinética , Inibidores da Bomba de Prótons/administração & dosagem , Transplantados , Adulto , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêuticoRESUMO
Mycophenolic acid (MPA) has being used clinically for organ rejection prophylaxis. Recent studies have revealed that MPA can also act as a chemo-sensitizing agent when used in combination with various chemotherapeutic agents in a cancer type-specific manner, including with oxaliplatin on oral squamous cell carcinoma (OSCC) cells. To prepare for the analysis of a novel drug delivery route for MPA absorption via oral mucosa as a potential therapeutic product, it is essential to develop and validate a highly sensitive analytical method for the quantification of MPA in biological samples for pharmacokinetic and tissue distribution studies. Herein, we report a sensitive, specific and reproducible UPLC-MS/MS method to do so. Blank rat plasma or tongue tissue homogenates coupled with griseofulvin, as internal standard, was used for generating standard curves ranging from 0.5 to 1000 ng/mL (r > 0.9990) for both plasma and tongue tissue homogenates. The chromatographic separation was achieved by a reverse phase ACE Excel 2 Super C18 column with a flow rate of 0.4 mL/min under gradient elution. Mass detection was performed under positive ionization electrospray. Inter- and intra-day accuracy and precision of the assay were ≤15% in both plasma and tongue tissue homogenates. The matrix effect was non-significant and extraction recovery rates were within 87.99% and 109.69% in plasma and tongue homogenates, respectively. The validity of this assay has been confirmed by measuring MPA in rat plasma for pharmacokinetics following intravenous administration of 0.5 mg/kg of mycophenolate sodium, as well as monitoring MPA in rat tongues for tissue distribution and detecting MPA that diffused into systemic circulation following a 4-h transmucosal delivery of 357 µg/cm2 of mycophenolate sodium.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ácido Micofenólico/análise , Ácido Micofenólico/farmacocinética , Espectrometria de Massas em Tandem/métodos , Língua/metabolismo , Animais , Modelos Lineares , Masculino , Ácido Micofenólico/sangue , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual , Língua/químicaRESUMO
BACKGROUND: There is little data on mycophenolic acid (MPA) pharmacokinetics and pharmacogenomics and optimal MPA exposure in lupus nephritis (LN) patients during long-term maintenance. METHODS: We measured blood MPA levels at 1, 2, 4, 8, 10 and 12-h post-dose (i.e. C1, C2, C4, C8, C10 and C12) in 88 stable LN patients receiving maintenance prednisolone and mycophenolate mofetil, repeated every 6 months. The relationship between MPA exposure and single nucleotide polymorphisms (SNPs) of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2; rs2273697, rs3740066, rs717620 and rs17222723), organic anion-transporting polypeptides (OATPs; rs7311358 and rs4149117) and uridine diphosphate glucuronosyltransferase (UGT; rs17863762, rs6714486, rs17868320 and rs72551330) was also investigated. RESULTS: C1, C2 and C12 were 8.3 ± 6.6 , 7.2 ± 5.2 and 2.0 ± 1.4 mg/L and all correlated with the 12-h area under the curve (AUC0-12; r = 0.51, 0.85 and 0.73; P = 0.02, <0.001 and <0.001, respectively). C12 inversely correlated with hemoglobin, immunoglobulins and leukocyte levels (P < 0.05 for all). Five renal flares, 11 episodes of infection and 10 episodes of anemia (hemoglobin <10 g/dL) occurred over 96 weeks, with a corresponding C12 of 1.3 ± 0.5, 4.3 ± 2.6 and 2.9 ± 1.5 mg/L, respectively (versus 2.4 ± 1.2, 1.8 ± 1.2 and 1.7 ± 1.1 mg/L in patients without these complications; P = 0.041, <0.001 and 0.004). SNP rs2273697 A/G in the ABCC2 gene was associated with lower MPA exposure compared with G/G (1075.9 ± 239.9 versus 1891.5 ± 918.9 mgh/L per g/kg; P = 0.003). SNPs of OATP and UGT were unrelated to MPA level. CONCLUSION: MPA C12 correlates with the AUC0-12 and is related to renal flare, infection and anemia. SNP rs2273697 A/G is associated with lower MPA exposure.
Assuntos
Imunossupressores/farmacocinética , Nefrite Lúpica/tratamento farmacológico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Ácido Micofenólico/farmacocinética , Transportadores de Ânions Orgânicos/genética , Farmacogenética , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Nefrite Lúpica/sangue , Nefrite Lúpica/genética , Nefrite Lúpica/patologia , Masculino , Proteína 2 Associada à Farmacorresistência Múltipla , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/sangue , Estudos Prospectivos , Distribuição TecidualRESUMO
Objectives: To identify the prognostic predictive factor of complete renal response (CR) at week 12 by focusing on the plasma mycophenolic acid (MPA) concentration in induction therapy in lupus nephritis.Methods: We prospectively enrolled patients with biopsy-proven LN class III/IV who were hospitalized between 2016 and 2017. As an induction therapy, mycophenolate mofetil was continuously introduced at 2000 mg/day. We measured the MPA plasma concentration at two time points depending on the induction therapy phase, early (week 4) or middle (week 12). The association between these concentrations and CR rate at week 12 was evaluated.Results: Ten patients were enrolled. A significantly higher AUC0-12 between 0 and 12 h of MPA at the early phase was observed in the patients with CR at week 12 than in those without (p = .03). All the patients with high MPA-AUC0-12 (> 40 mg h/L) at the early phase achieved CR at week 12, but no such association was found at the middle phase. The multivariate analysis revealed that MPA-AUC0-12 was selected as an independent predictive factor of CR at week 12 (odds ratio: 1.12; 95% confidence interval: 1.01-1.45, p = .02).Conclusion: The high AUC0-12 of MPA at the early phase of induction therapy may predict good renal response.
Assuntos
Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Ácido Micofenólico/sangue , Indução de Remissão/métodos , Adulto , Biomarcadores/sangue , Feminino , Humanos , Nefrite Lúpica/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
An innovative electrochemical sensor was proposed for simultaneous determination of mycophenolate mofetil (Mph) and tacrolimus (TAC) for the first time. A novel sensor based on electro-polymerization of multi-walled carbon nanotubes (MWCNTs) and a novel Cu-1N-allyl-2-(2,5-dimethoxyphenyl)-4,5-diphenyl-1H-imidazole metal organic framework (Cu-ADPPI MOF) on disposable pencil graphite electrode (dPGE). Many techniques were used to characterize the electrochemical activity and surface structure of the fabricated sensor. The proposed sensor exhibited good catalytic performance towards Mph and TAC oxidation due to the synergistic effect. Under optimal conditions, the proposed sensor has achieved a linear range of 0.85-155 × 10-8 M and 1.1-170.0 × 10-8 M with LODs of 0.28 × 10-8 M and 0.36 × 10-8 M for Mph and TAC, respectively. The designated sensor showed good reproducibility, repeatability, stability, and selectivity for the determination of Mph and TAC. Moreover, the simultaneous determination of Mph and TAC in different human biological fluids was carried out with acceptable results. As a result, the proposed sensor opens a new venue for the use of electro-polymerized MOFs in combination with other conductive materials such as MWCNTs for electrochemical sensing of different analytes with the desired sensitivity and selectivity. Graphical abstract Construction of disposable graphite electrode, based on electro-deposition of multilayer films of multi-walled carbon nanotubes and a new generation of Cu-MOFs, for simultaneous analysis of tacrolimus and mycophenolate mofetil for the first time.