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2.
J Ethnopharmacol ; 265: 113251, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32810615

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Application of cyclosporine A (CsA) as a rescue treatment in acute severe ulcerative colitis (UC) is limited by its narrow therapeutic window and great interpatient variability. As a substrate of cytochrome P450 3A enzyme (CYP3A) and P-glycoprotein (P-gp), the oral pharmacokinetics of CsA is susceptible to disease status and concomitant medications. Combined treatment with ginseng, a famous medicinal herb frequently prescribed for ameliorating abnormal immune response in many diseases including UC, showed immunologic safety in CsA-based immunosuppression. AIM OF THE STUDY: Since the therapeutic levels of CsA can be achieved within 24 h, this study first assessed the impact of acute colitis and ginseng intervention on the single oral dose pharmacokinetics of CsA and explored the underlying mechanisms in dextran sulfate sodium (DSS)-induced colitis rats and Caco-2 cells. MATERIALS AND METHODS: Rats received drinking water (normal group), 5% DSS (UC group), or 5% DSS plus daily oral ginseng extract (GS+UC group). On day 7, GS+UC group only received an oral dose of CsA (5 mg/kg), while animals of normal or UC group received an oral, intravenous (1.25 mg/kg), or intraperitoneal dose of CsA (1.25 mg/kg), respectively. Blood, liver/intestine tissues and fecal samples were collected for determining CsA and main hydroxylated metabolite HO-CsA or measuring hepatic/intestinal CYP3A activity. Caco-2 cells were incubated with gut microbial culture supernatant (CS) of different groups or ginseng (decoction or polysaccharides), and then CYP3A, P-gp and tight junction (TJ) proteins were determined. RESULTS: Oral CsA exhibited enhanced absorption, systemic exposure and tissue accumulation, and lower fecal excretion, while intravenous or intraperitoneal CsA showed lower systemic exposure and enhanced distribution, in colitis rats. Diminished intestinal and hepatic P-gp expression well explained the changes with DSS-induced colitis. Moreover, blood exposures of HO-CsA in both normal and colitis after oral dosing were significantly higher than intravenous/intraperitoneal dosing, supporting the dominant role of intestinal first-pass metabolism. Interestingly, colitis reduced CYP3A expression in intestine and liver but only potentiated intestinal CYP3A activity, causing higher oral systemic exposure of HO-CsA. Oral ginseng mitigated colitis-induced down-regulation of CYP3A and P-gp expression, facilitated HO-CsA production, biliary excretion and colonic sequestration of CsA, while not affected CsA oral systemic exposure. In Caco-2 cells, gut microbial CS from both colitis and GS+UC group diminished P-gp function, while ginseng polysaccharides directly affected ZO-1 distribution and suppressed TJ proteins expression, explaining unaltered oral CsA systemic exposure. CONCLUSIONS: DSS-induced colitis significantly altered oral CsA disposition through regulating intestinal and hepatic P-gp and CYP3A. One-week ginseng treatment enhanced colonic accumulation while not altered the systemic exposure of CsA after single oral dosing, indicating pharmacokinetic compatibility between the two medications.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Ciclosporina/farmacocinética , Panax/química , Extratos Vegetais/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Células CACO-2 , Colite Ulcerativa/fisiopatologia , Ciclosporina/administração & dosagem , Citocromo P-450 CYP3A/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Interações Ervas-Drogas , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
3.
Int J Nanomedicine ; 15: 7937-7949, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116510

RESUMO

Background: Cyclosporine A (CsA) is an exceptional immunosuppressant used for the treatment of immune disorders. Niosomal vesicles are promising drug carriers that are formed by self-association of nonionic surfactants and cholesterol in an aqueous phase. The objective of the study was to formulate combined nonionic surfactant based vesicles and to evaluate their in vitro characterization, release studies and in vivo studies. Materials and Methods: Five niosomal formulations (F7 to F11) were prepared using the thin film hydration method. The molar ratio of cholesterol and non-ionic surfactant taken was 1:1. In formulation F10, the combination of surfactants Span 20 and Brij 35 was used. The niosomes were characterized by zeta sizer and SEM for particle size analysis, in vitro drug release and stability studies. The pharmacokinetic studies were conducted on healthy albino rabbits. Results: The size of niosome was found in the range of 427.1 nm to 972.3 nm. SEM image of optimized formulations F10 exhibit the spherical nature of niosomal vesicles. DSC thermograms of niosomal formulations exhibited a broadened endothermic peak. The stability study exhibited that all formulations are stable and negligible change of vesicle size and entrapment was observed with time. The percentage drug release was significantly higher as compared to CsA plain dispersion for all niosomal formulations at pH 1.2 and 7.4. The release kinetic behavior showed that all preparations were best described by zero order and can release active ingredient in a sustained manner. The pharmacokinetic data showed the test formulation (F10) possessed greater bioavailability as compared to the reference formulation (CsA aqueous dispersion). Conclusion: The formulation F10 demonstrated a comparatively more delayed rate of release with enhanced dissolution as compared to a single surfactant scheme. The F10 formulation can be a remarkable nanotechnology for prolonged delivery of CsA orally with improved dissolution profile and bioavailability.


Assuntos
Portadores de Fármacos/química , Imunossupressores/química , Imunossupressores/farmacologia , Tensoativos/química , Animais , Disponibilidade Biológica , Colesterol/química , Ciclosporina/administração & dosagem , Ciclosporina/química , Ciclosporina/farmacocinética , Ciclosporina/farmacologia , Liberação Controlada de Fármacos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Lipossomos , Tamanho da Partícula , Coelhos
4.
Eur J Drug Metab Pharmacokinet ; 45(6): 749-760, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32886348

RESUMO

BACKGROUND AND OBJECTIVE: Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this study was to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C0/D), during 6-12 months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C0/D, the study aimed to estimate the combined effect of tacrolimus IPV and C0/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36 months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods. METHODS: The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36 months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C0/D during 6-12 months post-transplantation. RESULTS: The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C0/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C0/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C0/D. Patients with high IPV/low C0/D had significantly reduced graft survival compared to the other tacrolimus IPV/C0/D combination groups (i.e., high IPV/high C0/D, low IPV/low C0/D, low IPV/high C0/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint. CONCLUSION: The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Tacrolimo/farmacocinética , Tacrolimo/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Feminino , Genótipo , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Imunossupressores/administração & dosagem , Isoenzimas/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Estudos Retrospectivos , Tacrolimo/administração & dosagem
5.
Int J Nanomedicine ; 15: 5603-5612, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848390

RESUMO

Introduction: Organ transplantation is a critically important procedure, which requires immune modulation by using immunosuppressants. Development of nanoparticles is an emerging and beneficial engineering process to increase the dissolution rate of poorly soluble immunosuppressants as well as to provide controlled release for better therapeutic outcomes. Method: Currently, the nanoprecipitation method was employed to fabricate ß-cyclodextrin (ßCD) facilitated mycophenolate mofetil (MMF)-loaded solid lipid nanoparticles (SLNPs). The prime objectives of the study included, improvement of the dissolution profile of poorly aqueous soluble drug and controlled release from the SLNs to provide steady state drug concentration. Drug release from the prepared SLNs was assessed in two different media, ie, acidic buffer at pH 1.2 and phosphate buffer at pH 7.2 using USP dissolution apparatus for 12 h, followed by the evaluation of drug release mechanism and pattern by applying kinetic models. Results: Justifiably, in acidic medium, the release was found to be 12% more (68%) in comparison to that in basic medium (56%). However, in both dissolution media, drug release was independent of initial concentration (R2>0.95) with non-Fickian type of diffusion mechanism. The outcomes of the study have exhibited that prepared formulations were in nanosized range (80-170 nm) with a net charge of ±23 charge on their surface. They possessed fairly uniform surface with acceptable polydispersity index (0.23±0.09). Scanning electron microscopy (SEM) analysis illustrated that the nanoparticles had uniform particle size and shape. Discussion: The findings show potential applications of the nanoparticles and the method for the development of SLNPs in controlled release of MMF for better therapeutic outcomes. Conclusively, the prepared SLNPs were well designed in nanosized ranges and justifying the once daily controlled release formulation dose of MMF to enhance patient compliance.


Assuntos
Portadores de Fármacos/química , Imunossupressores/farmacocinética , Ácido Micofenólico/farmacocinética , Nanopartículas/química , Disponibilidade Biológica , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Difusão , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Imunossupressores/química , Lipídeos/química , Microscopia Eletrônica de Varredura , Ácido Micofenólico/química , Nanopartículas/administração & dosagem , Tamanho da Partícula , Solubilidade , beta-Ciclodextrinas/química
6.
S Afr Med J ; 110(2): 159-166, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32657689

RESUMO

BACKGROUND: Tacrolimus forms the cornerstone for immunosuppression in solid-organ transplantation. It has a narrow therapeutic window with wide inter- and intra-patient variability (IPV). Cytochrome P-450 3A5 (CYP3A5) is the main enzyme involved in tacrolimus metabolism, and rs776746A>G is the most frequently studied polymorphism in the CYP3A5 gene. The rs776746A>G (i.e. CYP3A5*3) single-nucleotide polymorphism in CYP3A5 alters tacrolimus predose trough concentration (C0) and may also affect IPV, which may lead to immune- and/or drug-mediated allograft injury. CYP3A5*3 may result in absent (*3/*3), partial (*1/*3) or normal (*1/*1) CYP3A5 expression. The effect of CYP3A5*3 on tacrolimus exposure and variability has not been examined in South African (SA) transplant recipients. OBJECTIVES: To determine the frequencies and effect of CYP3A5 and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) polymorphisms on tacrolimus C0/dose ratios in different ethnic groups attending a tertiary renal transplant clinic in SA, and other factors that may explain inter- and IPV in tacrolimus C0. METHODS: All consenting stable renal transplant recipients on tacrolimus at the Livingstone Hospital Renal Unit in Port Elizabeth, SA, were included. Tacrolimus concentrations were obtained using a microparticle enzyme immunoassay method (ARCHITECT analyser, Abbott Laboratories). Polymerase chain reaction/restriction fragment length polymorphism was used to genotype for CYP3A5*3 and *6 allelic variants. RESULTS: There were 43 participants (35% black African, 44% mixed ancestry and 21% white), with a mean age of 44.5 years, median duration post-transplant of 47 months and median (interquartile range) creatinine and estimated glomerular filtration rate levels of 118 (92 - 140) µmol/L and 62 (49 - 76) mL/min at study inclusion. The mean tacrolimus C0 in the study was 6.7 ng/mL, with no difference across the different ethnic groups. However, the mean total daily dose of tacrolimus required was 9.1 mg (0.12 mg/kg), 7.2 mg (0.09 mg/kg) and 4.3 mg (0.06 mg/kg) in black, mixed-ancestry and white patients, respectively (p=0.017). The frequencies for CYP3A5 expressors (i.e. CYP3A5*1/*1 + CYP3A5*1/*3 genotypes) were 72%, 100%, 76% and 12% for all patients combined and black, mixed-ancestry and white patients, respectively. The frequencies for CYP3A5 non-expressors (i.e. CYP3A5*3/*3 genotypes) were 0%, 24% and 88% among the black, mixed-ancestry and white patients, respectively. None of the patients carried the CYP3A5*6 allele. CYP3A5*1/*1 and CYP3A5*1/*3 genotype carriers required a two-fold increase in dose compared with the non-expressor genotype carriers, CYP3A5*3/*3 (p<0.05). CYP3A5*3/*3 carriers also demonstrated higher IPV than CYP3A5*1/*1 and *1/*3 carriers (18.1% v. 14.2%; p=0.125). CONCLUSIONS: Compared with global transplant populations, SA renal transplant recipients demonstrated a very high rate of CYP3A5 expression, with a significant impact on tacrolimus pharmacokinetics. Genetic variation in CYP3A5 expression affects tacrolimus dosing requirements, and knowing the CYP3A5 genotype of transplant patients may allow better dose prediction compared with current standard dosing recommendations in a multi-ethnic population. Overall, black African patients required higher doses of tacrolimus than their white counterparts. While further prospective studies are needed to better evaluate dosing algorithms, it would appear that the starting dose of tacrolimus should be higher in black and mixed-race patients.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Tacrolimo/administração & dosagem , Adulto , Estudos de Coortes , Grupos de Populações Continentais/genética , Relação Dose-Resposta a Droga , Feminino , Variação Genética , Genótipo , Humanos , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , África do Sul , Tacrolimo/farmacocinética
7.
Expert Opin Pharmacother ; 21(12): 1399-1405, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32543241

RESUMO

INTRODUCTION: In recent years there has been a dramatic rise in available disease-modifying therapies for the treatment of relapsing multiple sclerosis (MS). Dimethyl fumarate (DMF) is an oral drug approved by the FDA for relapsing MS with unique immunomodulatory and cytoprotective effects. AREAS COVERED: Herein, the authors provide the reader with a review of the literature obtained via a PubMed database search and provide their expert opinion on the use of DMF in clinical practice. The article details DMF's mechanism of action, long-term data on efficacy, tolerability and safety. EXPERT OPINION: Since approval, growing experience with DMF in clinical practice demonstrates a combination of efficacy, ease of administration along with an acceptable safety profile. The authors believe that DMF is a valuable long-term treatment option in patients with relapsing MS. However, long-term follow up studies are needed to provide further data on progressive multifocal leukoencephalopathy (PML) risk stratification for MS patients on treatment with DMF. Indeed, despite the strong association with lymphopenia, not all patients with DMF associated PML experienced prolonged overall lymphopenia, suggesting that additional predictive metrics are still needed.


Assuntos
Fumarato de Dimetilo/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Administração Oral , Ensaios Clínicos como Assunto , Fumarato de Dimetilo/administração & dosagem , Fumarato de Dimetilo/efeitos adversos , Fumarato de Dimetilo/farmacocinética , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Leucopenia/induzido quimicamente , Assistência de Longa Duração , Esclerose Múltipla Recidivante-Remitente/imunologia , Resultado do Tratamento
8.
Vascul Pharmacol ; 130: 106682, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32438078

RESUMO

No data are available on rivaroxaban use in renal transplant recipients and on its surmised interaction with immunosuppressants. The aim was to investigate potential interactions between rivaroxaban and immunosuppressants in this setting. Renal transplant recipients with a stable renal function treated with rivaroxaban and tacrolimus with or without everolimus were investigated. All drugs and creatinine concentrations were determined daily for 2 weeks after the start of anticoagulation. Blood samples were drawn at 8.00 am and 3-4 h later for trough and peak concentrations, respectively. Bleeding and thrombotic events were recorded during a minimum follow-up of 6 months. In 8 renal transplant patients, rivaroxaban levels showed a predictable pharmacokinetic trend, both at Ctrough (30-61 µg/L) and at Cpeak (143-449 µg/L), with limited variability in the 25th-75th percentile range. Tacrolimus (Ctrough 3-13 µg/L; Cpeak 3-16 µg/L), everolimus (Ctrough 3-11 µg/L; Cpeak 5-17 µg/L) and creatinine concentrations were stable as well. Immunosuppressors variability before and after rivaroxaban were 30% and 30% for tacrolimus, 27% and 29% for everolimus, respectively, as well as 14% and 3% for creatinine. For rivaroxaban monitoring, the reference change value better performed in identifying significant variations of its concentration. No patient had bleeding or thrombotic events, worsening of renal graft function, and signs of immunosuppressants toxicity during a mean follow-up of 23 (9-28) months. In conclusion, rivaroxaban does not seem to interact with tacrolimus and everolimus in renal transplant recipients. Both anticoagulant and immunosuppressive effects seem warranted, without major bleeding complications and effect on the graft function.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Everolimo/farmacocinética , Inibidores do Fator Xa/farmacocinética , Imunossupressores/farmacocinética , Transplante de Rim , Rivaroxabana/farmacocinética , Tacrolimo/farmacocinética , Trombose Venosa/tratamento farmacológico , Idoso , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Coagulação Sanguínea/efeitos dos fármacos , Interações Medicamentosas , Monitoramento de Medicamentos , Everolimo/efeitos adversos , Everolimo/sangue , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/sangue , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Hemorragia/induzido quimicamente , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Rivaroxabana/efeitos adversos , Rivaroxabana/sangue , Tacrolimo/efeitos adversos , Tacrolimo/sangue , Resultado do Tratamento , Trombose Venosa/sangue , Trombose Venosa/diagnóstico
9.
Transplantation ; 104(7): e208-e213, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32235257

RESUMO

BACKGROUND: Histologic criteria for diagnosing acute rejection in vascularized composite tissue allograft (VCA) have been established by the Banff 2007 Working Classification of Skin-Containing Composite Tissue Allograft, but the role of early vascular lesions in graft rejection warrants additional analysis. METHODS: We performed a retrospective study of 34 skin biopsies performed over 430 d for rejection surveillance, in Canada's first face allotransplant recipient. Three observers reviewed all biopsies to assess the nature and intensity of the inflammatory skin infiltrate. A complete histological and immunohistochemical review of the vascular components was performed with a focus on lymphocytic vasculitis, intravascular fibrin, vessel caliber, extent of injury, C4d positivity, and inflammatory cell phenotyping. We then correlated these data points to clinical and immunosuppression parameters. RESULTS: Acute vascular damage in biopsies that would be classified as mild acute rejection correlates with troughs in immunosuppression and subsides when immunosuppressive tacrolimus doses are increased. Grade 0 Banff rejection and Grade I without lymphocytic vasculitis were almost indistinguishable, whereas Grade I with lymphocytic vasculitis was an easy and reproducible histologic finding. CONCLUSIONS: Our results highlight the possible relevance of vascular injury in the context of VCA, as its presence might underlie a more aggressive form of immune rejection. If these findings are validated in other VCA patients, vascular injury in mild rejection might warrant a different clinical approach.


Assuntos
Transplante de Face/efeitos adversos , Rejeição de Enxerto/diagnóstico , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem , Vasculite/complicações , Idoso , Biópsia , Canadá , Aloenxertos Compostos/irrigação sanguínea , Aloenxertos Compostos/patologia , Relação Dose-Resposta a Droga , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Humanos , Imunossupressores/farmacocinética , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Pele/irrigação sanguínea , Pele/patologia , Tacrolimo/farmacocinética , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Vasculite/diagnóstico , Vasculite/tratamento farmacológico , Vasculite/imunologia
10.
Am J Transplant ; 20(7): 1896-1901, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32337790

RESUMO

The current coronavirus disease 2019 (COVID-19) pandemic requires extra attention for immunocompromised patients, including solid organ transplant recipients. We report on a case of a 35-year-old renal transplant recipient who suffered from a severe COVID-19 pneumonia. The clinical course was complicated by extreme overexposure to the mammalian target of rapamycin inhibitor everolimus, following coadministration of chloroquine and lopinavir/ritonavir therapy. The case is illustrative for dilemmas that transplant professionals may face in the absence of evidence-based COVID-19 therapy and concurrent pressure for exploration of experimental pharmacological treatment options. However, the risk-benefit balance of experimental or off-label therapy may be weighed differently in organ transplant recipients than in otherwise healthy COVID-19 patients, owing to their immunocompromised status and potential drug interactions with immunosuppressive therapy. With this case report, we aimed to achieve increased awareness and improved management of drug-drug interactions associated with the various treatment options for COVID-19 in renal transplant patients.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/terapia , Everolimo/farmacocinética , Falência Renal Crônica/complicações , Transplante de Rim , Pneumonia Viral/complicações , Pneumonia Viral/terapia , Transplantados , Adulto , Antivirais/administração & dosagem , Antivirais/farmacocinética , Betacoronavirus , Cloroquina/administração & dosagem , Cloroquina/farmacocinética , Combinação de Medicamentos , Interações Medicamentosas , Everolimo/administração & dosagem , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Falência Renal Crônica/cirurgia , Lopinavir/administração & dosagem , Lopinavir/farmacocinética , Masculino , Países Baixos , Pandemias , Radiografia Torácica , Ritonavir/administração & dosagem , Ritonavir/farmacocinética , Resultado do Tratamento
11.
Toxicol Appl Pharmacol ; 396: 115000, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32275916

RESUMO

The pharmacokinetics of Tacrolimus is characterized by a high interindividual variability that is mainly explained by pharmacogenetics biomarkers. The aims were to develop a population pharmacokinetic model (Pk pop) taking into account post-transplant phases (PTP), CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms on Tac pharmacokinetics in adult kidney transplant patients. The Pk pop study was performed using a nonparametric approach (Pmetrics*). The influence of covariates (age, weight, sex, hematocrit and CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms) was tested on the model's Pk parameters. The performance of the final model was assessed using an external dataset. A one-compartment model (Vd: volume of distribution, CL: Tac Clearance) was found to correctly describe the evolution of the C0/D regardless of the PTP. The influence of the covariates has shown that only the CYP3A4*1B and CYP3A4*22 polymorphisms were significantly associated only with CL, regardless of PTP (p = .04 and 0.02, respectively). Only the CYP3A4*22 polymorphism influenced CL during early PTP (P1: the first three months, p = .02). During the late PTP (P2: >3 months), only CYP3A4 polymorphisms were found to affect CL (p = .03 for both). The external validation of the final model, including both CYP3A4 polymorphisms, showed an acceptable predictive performance during P1 and P2. We developed and validated a tac Pk pop model including both CYP3A4*22 and CYP3A4*1B polymorphisms, taking into account PTP. This model was very useful in the Tac dose proposal in this population on any PT day but could not be used in other organ transplants due to pharmacokinetic differences.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , Transplante de Rim , Tacrolimo/farmacocinética , Adulto , Estudos Transversais , Citocromo P-450 CYP3A/metabolismo , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Taxa de Depuração Metabólica/genética , Pessoa de Meia-Idade , Testes Farmacogenômicos , Polimorfismo Genético/genética , Tunísia , Adulto Jovem
12.
Pharm Res ; 37(3): 64, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32140879

RESUMO

PURPOSE: The aim of the present study was to develop a new multi-unit dosage formulation, Universal ORbicular Vehicle (UniORV), to improve the biopharmaceutical properties of tacrolimus (TAC). METHODS: TAC-loaded UniORV (UO/TAC) was produced by the dripping and gelling of a solution comprising TAC, gelatin, starch syrup, and triethyl citrate at 0.5 w/w% drug loading. Its microstructure was elucidated by polarized light microscopy and the Raman mapping technique. The pharmacokinetic profiles of TAC after the oral administration of UO/TAC were evaluated in rats and healthy humans. RESULTS: The dissolution behavior of UO/TAC was similar to that of commercial capsules, and the formation of nanoparticles was detected by TEM in dissolved media. In a stability study on UO/TAC, only 2.6 and 4.7% decreases in TAC concentrations were observed at 40± 2°C/75 ± 5% relative humidity for 4 months and at 50± 2°C for 2 months, respectively. A pharmacokinetic study on rats revealed a 30-fold higher AUC than that with crystalline TAC. A randomized double-blind crossover study on 8 healthy males showed that UniORV achieved a 1.4-fold increase in AUC and 34% decrease in inter-individual variation from the reference formulation. CONCLUSION: The new dosage form UniORV is a promising approach to improve the dissolution, amorphous stability, and biopharmaceutical properties of TAC, which is a poorly water-soluble drug.


Assuntos
Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Veículos Farmacêuticos/química , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Administração Oral , Adulto , Animais , Citratos/química , Estudos Cross-Over , Método Duplo-Cego , Composição de Medicamentos , Liberação Controlada de Fármacos , Gelatina/química , Humanos , Imunossupressores/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Amido/química , Tacrolimo/sangue , Adulto Jovem
13.
PLoS One ; 15(3): e0230195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163483

RESUMO

Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation. A non-parametric population pharmacokinetic model was applied to explore TAC pharmacokinetics in blood and PBMC. Concurrently, calcineurin activity was measured in PBMC. Influence of donor and recipient genetic polymorphisms of ABCB1, CYP3A4 and CYP3A5 on TAC exposure was assessed. Recipient ABCB1 polymorphisms 1199G>A could influence TAC whole blood and intracellular exposure (p<0.05). No association was found between CYP3A4 or CYP3A5 genotypes and TAC whole blood or intracellular concentrations. Finally, intra-PBMC calcineurin activity appeared incompletely inhibited by TAC and less than 50% of patients were expected to achieve intracellular IC50 concentration (100 pg/millions of cells) at therapeutic whole blood concentration (i.e.: 4-10 ng/mL). Together, these data suggest that personalized medicine regarding TAC therapy might be optimized by ABCB1 pharmacogenetic biomarkers and by monitoring intracellular concentration whereas the relationship between intracellular TAC exposure and pharmacodynamics biomarkers more specific than calcineurin activity should be further investigated.


Assuntos
Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Leucócitos Mononucleares/metabolismo , Tacrolimo/farmacocinética , Tacrolimo/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Citocromo P-450 CYP3A/genética , Feminino , Genótipo , Humanos , Imunossupressão/métodos , Transplante de Fígado/métodos , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos , Testes Farmacogenômicos/métodos , Polimorfismo de Nucleotídeo Único/genética
14.
Medicine (Baltimore) ; 99(12): e19441, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195940

RESUMO

We hypothesized that area under the concentration time curve (AUC(0-12)) is more accurate pharmacokinetic predictor vs trough level of mycophenolic acid (C0).Study was performed at the University Hospital of Limoges (France) and included 238 renal recipients aged 22 to 82 years. Risk of nephropathy was evaluated by analyzing data of protocol biopsies according to the Banff 97 classification.Assessment of immunosuppressants' exposures was based on the calculation of the mean of AUC(0-12). The AUC(0-12) was estimated using a Bayesian estimator and a 3-point limited sampling strategy. Cyclosporine and tacrolimus analyses were performed using liquid chromatography-mass spectrometry method. The measurement of total mycophenolic acid was performed using a validated high-performance liquid chromatography method with ultraviolet detection. IBM SPSS 20.0 was used for statistical analysis.The most accurate dosing of mycophenolate mofetil (MMF) was observed in patients receiving MMF with tacrolimus, 70.6% of patients' AUC(0-12) exposures were within the therapeutic range. The highest rates of low dosing were observed in patients receiving MMF with cyclosporine, 30.9% of patients had AUC(0-12) exposures below the therapeutic range. The assessment of AUC(0-12) revealed 38% of chronic nephropathy cases, while C0 enables to identify only 20% of chronic nephropathy cases.Probability test results showed that more likely AUC(0-12) and C0 will be maintained within the therapeutic width if patients receive MMF with tacrolimus vs MMF with cyclosporine: 0.6320 vs 0.6410 for AUC(0-12) determination and 0.8415 vs 0.4827 for C0 determination.Combination of MMF with tacrolimus is dosed more precisely vs dosing of MMF with cyclosporine. 72 (70.6%) patients AUC(0-12) and 79 (77.5%) patients C0 out of 102 patients were within the therapeutic range. The AUC(0-12) monitoring of mycophenolic acid in patients receiving MMF with tacrolimus or in patients receiving MMF with cyclosporine enabled to identify more overdosing and possible risky cases.Study results show that standard MMF dosing without monitoring and with mycophenolic acid level within the therapeutic width is possible and demonstrates less risky cases in patients receiving MMF with tacrolimus, while patients receiving MMF with cyclosporine should be intensively monitored to achieve the highest safety. However, AUC(0-12) monitoring is advised showing better compliance vs C0 monitoring.


Assuntos
Ciclosporina/uso terapêutico , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Ácido Micofenólico/farmacocinética , Tacrolimo/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Ciclosporina/administração & dosagem , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Tacrolimo/administração & dosagem
15.
Eur J Pharm Sci ; 145: 105237, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001346

RESUMO

BACKGROUND: Diverse tacrolimus population pharmacokinetic (popPK) models in adult liver transplant recipients have been established to describe the PK characteristics of tacrolimus in the last two decades. However, their extrapolated predictive performance remains unclear. Therefore, in this study, we aimed to evaluate their external predictability and identify their potential influencing factors. METHODS: The external predictability of each selected popPK model was evaluated using an independent dataset of 84 patients with 572 trough concentrations prospectively collected from Huashan Hospital. Prediction- and simulation-based diagnostics and Bayesian forecasting were conducted to evaluate model predictability. Furthermore, the effect of model structure on the predictive performance was investigated. RESULTS: Sixteen published popPK models were assessed. In prediction-based diagnostics, the prediction error within ± 30% was below 50% in all the published models. The simulation-based normalised prediction distribution error test and prediction- and variability-corrected visual predictive check indicated large discrepancies between the observations and simulations in most of the models. Bayesian forecasting showed improvement in model predictability with two to three prior observations. Additionally, the predictive performance of the nonlinear Michaelis-Menten model was superior to that of linear one- and two-compartment models with first-order elimination, indicating the underlying nonlinear kinetics of tacrolimus in liver transplant recipients, which was consistent with the findings in adult kidney transplant recipients. CONCLUSIONS: The published models performed inadequately in prediction- and simulation-based diagnostics. Bayesian forecasting may improve the predictive performance of the models. Furthermore, nonlinear kinetics of tacrolimus may be mainly caused by the properties of the drug itself, and incorporating nonlinear kinetics may be considered to improve model predictability.


Assuntos
Imunossupressores/farmacocinética , Transplante de Fígado , Modelos Biológicos , Tacrolimo/farmacologia , Transplantados , Adulto , Humanos , Transplante de Fígado/efeitos adversos , Transplante de Fígado/tendências
16.
Nat Rev Rheumatol ; 16(3): 167-178, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32055040

RESUMO

The introduction of biologic DMARDs into rheumatology has resulted in a substantial reduction of the burden of many rheumatic diseases. In the slipstream of the success achieved with these biologic DMARDs, some conventional immunosuppressive drugs have also found use in new indications. Notably, mycophenolate mofetil, azathioprine and tacrolimus have made their way from solid organ transplantation drugs to become useful assets in rheumatology practice. Mycophenolate mofetil and azathioprine inhibit the purine pathway and subsequently diminish cell proliferation. Both drugs have a pivotal role in the treatment of various rheumatic diseases, including lupus nephritis. Tacrolimus inhibits lymphocyte activation by inhibiting the calcineurin pathway. Mycophenolate mofetil and tacrolimus are, among other indications, increasingly being recognized as useful drugs in the treatment of interstitial lung disease in systemic rheumatic diseases and skin fibrosis in systemic sclerosis. A broad array of trials with mycophenolate mofetil, azathioprine and/or tacrolimus are ongoing within the field of rheumatology that might provide further novel avenues for the use of these drugs. In this Review, we discuss the historical perspective, pharmacodynamics, clinical indications and novel avenues for mycophenolate mofetil, azathioprine and tacrolimus in rheumatology.


Assuntos
Azatioprina/uso terapêutico , Ácido Micofenólico/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Reumatologia , Tacrolimo/uso terapêutico , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Azatioprina/farmacocinética , Quimioterapia Combinada , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Ácido Micofenólico/farmacocinética , Tacrolimo/farmacocinética
17.
Int J Mol Sci ; 21(3)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013193

RESUMO

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Citocromo P-450 CYP3A/genética , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/farmacocinética , Tacrolimo/farmacocinética , Adulto , Idoso , Bases de Dados Genéticas , Feminino , Genótipo , Mutação em Linhagem Germinativa , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Transplante Homólogo , Adulto Jovem
18.
Anal Bioanal Chem ; 412(4): 1011-1024, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31897563

RESUMO

Cabbage flower-like Ho3+/NiO nanostructure (CFL-Ho3+/NiO NSs) with significant electrocatalytic oxidation has been published for the first time. First, structure and morphology of CFL-Ho3+/NiO-NSs have been described by XRD, SEM, and EDX methods. Then, CFL-Ho3+/NiO-NSs have been applied as a modifier for simultaneous electrochemical detection of methotrexate (MTX) and carbamazepine (CBZ). Functions of the modified electrode have been dealt with through electrochemical impedance spectroscopy (EIS). It has been demonstrated that the electrode response has been linear from 0.001-310.0 µM with a limit of detection of 5.2 nM and 4.5 nM (3 s/m) through DPV for MTX and CBZ. Diffusion coefficient (D) and heterogeneous rate constant (kh) have been detected for MTX and CBZ oxidation at the surface of the modified electrode. Moreover, CFL-Ho3+/NiO-NS/GCE has been employed for determining MTX and CBZ in urine and drug specimens. Outputs showed the analyte acceptable recovery. Therefore, the electrode could be applied to analyze both analytes in drug prescription and clinical laboratories. Graphical abstract Electrochemical sensor based on bifunctional cabbage flower-like Ho3+/NiO nanostructures modified glassy carbon electrode for simultaneous detecting methotrexate and carbamazepine was fabricated.


Assuntos
Analgésicos não Entorpecentes/farmacocinética , Carbamazepina/farmacocinética , Monitoramento de Medicamentos/métodos , Imunossupressores/farmacocinética , Metotrexato/farmacocinética , Analgésicos não Entorpecentes/análise , Analgésicos não Entorpecentes/sangue , Analgésicos não Entorpecentes/urina , Carbamazepina/análise , Carbamazepina/sangue , Carbamazepina/urina , Técnicas Eletroquímicas/métodos , Hólmio/química , Humanos , Imunossupressores/análise , Imunossupressores/sangue , Imunossupressores/urina , Limite de Detecção , Metotrexato/análise , Metotrexato/sangue , Metotrexato/urina , Nanoestruturas/química , Níquel/química , Oxirredução , Comprimidos
19.
Ann Transplant ; 25: e920225, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31974333

RESUMO

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 terapêutico
20.
Ann Pharmacother ; 54(7): 652-661, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31888346

RESUMO

Background: Tacrolimus (TAC) is widely used after liver transplantation, but the therapeutic window is narrow. Objective: The purpose was to study both donor and recipient CYP3A5*3 genotypes affecting TAC apparent clearance rate (CL/F) and investigate a TAC population pharmacokinetic (PPK) model in Chinese liver transplant recipients for potential starting-dose individualized medication. Methods: A data set of 721 TAC concentrations was obtained from 43 adult liver transplant recipients. The TAC PPK model was analyzed using nonlinear mixed-effects modeling. Potential covariates, including demographic characteristics, physiological and pathological data, concomitant medications, and CYP3A5*3 genotype, were evaluated. The final model was validated using normalized prediction distribution errors and bootstrapping. Results: A 2-compartment model with first-order absorption and elimination was used to describe TAC disposition. Population estimates of TAC, CL/F, apparent central distribution volume (V2/F), rate of absorption (Ka), and apparent peripheral distribution volume (V3/F) were 18.1 L/h (12%), 72.7 L (34%), 0.163 h-1 (17%), and 412 L (21%), respectively. The model and estimated parameters were found to be stable. Other covariates did not influence TAC CL/F. Both donor and recipient CYP3A5*1 genotypes were significantly correlated with TAC clearance, and CL/F was 1.70-fold higher in both donor and recipient CYP3A5*1 carriers than in noncarriers among Chinese liver transplant recipients. Conclusion and Relevance: A PPK model of TAC was established in Chinese adult liver transplantation recipients for starting-dose individualized medication, which can be expanded to optimize clinical efficacy and minimize toxicity with therapeutic drug monitoring.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , Transplante de Fígado , Modelos Biológicos , Polimorfismo Genético , Tacrolimo/farmacocinética , Adulto , Grupo com Ancestrais do Continente Asiático , Monitoramento de Medicamentos , Feminino , Genótipo , Humanos , Imunossupressores/administração & dosagem , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Tacrolimo/administração & dosagem , Doadores de Tecidos , Transplantados
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