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1.
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
2.
Int J Clin Pharmacol Ther ; 58(1): 1-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31319907

RESUMO

OBJECTIVE: To establish a population pharmacokinetic (PopPK) model of cyclosporine A (CsA) in Chinese patients with nephrotic syndrome (NS) and to use the model to guide the adjustment of individualized dosage regimens. MATERIALS AND METHODS: 216 CsA therapeutic drug monitoring (TDM) concentration observations were collected from 127 Chinese patients with NS. The basic model was developed as a one-compartment PK model with first-order absorption and linear elimination. The first-order conditional estimation (FOCE) method was applied to establish the final model with covariates using NONMEM software. The final model was evaluated through internal validation including goodness-of-fit analysis and bootstrap method as well as external validation using 39 additional PK observations from 35 patients with NS. RESULTS: A PopPK model of CsA was established in Chinese NS patients with influence of body weight on clearance. The internal and external validation results showed that the final model was stable. CONCLUSION: The established population model adequately characterized the PK of CsA in Chinese patients and could support individualized medication during treatment of NS with CsA.


Assuntos
Ciclosporina/farmacocinética , Imunossupressores/farmacocinética , Síndrome Nefrótica/tratamento farmacológico , Grupo com Ancestrais do Continente Asiático , China , Humanos , Modelos Biológicos , Software
3.
J Oncol Pharm Pract ; 26(1): 5-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30854922

RESUMO

BACKGROUND: Posaconazole reduces the risk of invasive Aspergillus in transplant patients, but significantly inhibits tacrolimus metabolism. One study demonstrated that a three-fold dose reduction of tacrolimus was required to obtain therapeutic concentrations when used with posaconazole. However, with empiric dose reduction, there is a risk of subtherapeutic tacrolimus levels and subsequent graft failure or graft-versus-host disease. Overall, the existing data on the impact of posaconazole on tacrolimus pharmacokinetics is limited. OBJECTIVE: The purpose of this study is to determine whether tacrolimus doses should be decreased upon initiation of posaconazole in patients receiving an allogeneic stem cell transplant. METHODS: This is a retrospective chart review at an academic medical center. All allogeneic stem cell transplant adults who received concomitant posaconazole and tacrolimus from February 2016 through December 2017 were included. RESULTS: Seventy-nine patients identified using an internal electronic database were analyzed. The median time to therapeutic tacrolimus concentration was significantly longer in patients who did not receive an empiric dose reduction (0% DR, 10d; 1-30% DR, 4d; 31-65% DR, 5d; >65% DR, 4d; p = 0.0395). The rate of supratherapeutic levels was highest amongst patients who did not receive an empiric DR, and was noted to be significant compared to the group that had 31-65% DR (p < 0.001). CONCLUSION: This study validates our current practice of instituting an empiric 50% dose reduction of oral tacrolimus to 0.03 mg/kg/day when used concomitantly with posaconazole to achieve therapeutic levels in allogeneic stem cell transplant patients.


Assuntos
Antifúngicos/farmacocinética , Transplante de Células-Tronco Hematopoéticas/tendências , Imunossupressores/farmacocinética , Transplante de Células-Tronco/tendências , Tacrolimo/farmacocinética , Triazóis/farmacocinética , Adulto , Antifúngicos/administração & dosagem , Esquema de Medicação , Interações de Medicamentos/fisiologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Triazóis/administração & dosagem
4.
Pharm Res ; 37(1): 15, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31873806

RESUMO

PURPOSE: To explore the contribution of physiological characteristics to variability in ciclosporin pharmacokinetics in hematopoietic stem cell transplantation patients. METHODS: Clinical data from 563 patients were collected from centers in three regions. Ciclosporin concentrations were measured using immunoassays. The patients' demographics, hematological and biological indicators, coadministered drugs, region, and disease diagnosis were recorded from medical records. Data analysis was performed using NONMEM based on a one-compartment model to describe the pharmacokinetics of ciclosporin. The reliability and stability of the final model were evaluated using bootstrap resampling, goodness-of-fit plots, and prediction-corrected visual predictive checks. RESULTS: The population estimate of the clearance (CL) was 30.4 L/h, the volume of distribution (V) was 874.0 L and the bioavailability (F) was 81.1%. The between-subject variability in these parameters was 26.3, 68.0, and 110.8%, respectively. Coadministration of fluconazole, itraconazole, or voriconazole decreased CL by 17.6%, 28.4%, and 29.2%, respectively. Females' CL increased by approximately 12.0%. In addition, CL and V decreased with hematocrit, total protein, and uric acid increase, and CL also decreased with age and aspartate aminotransferase increase. However, CL increased with creatinine clearance increase. CONCLUSIONS: A multicenter-based population pharmacokinetic model of ciclosporin was established. The pharmacokinetics of ciclosporin exhibited discrepancies among different regions.


Assuntos
Ciclosporina/farmacocinética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Imunossupressores/farmacocinética , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Peso Corporal , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Feminino , Fluconazol/farmacologia , Neoplasias Hematológicas/terapia , Humanos , Itraconazol/farmacologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Reprodutibilidade dos Testes , Voriconazol/farmacologia
5.
Transplant Proc ; 51(9): 2971-2973, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607620

RESUMO

BACKGROUND: An extended-release formulation of tacrolimus designed for once-daily administration (LCP-TAC) is a new prolonged-release tacrolimus (TAC-PR) formulation using a drug delivery technology designed to enhance the bioavailability of drugs compared with TAC-PR. The aim of this study was to retrospectively compare de novo administration of LCP-TAC and TAC-PR for therapeutic trough levels and daily dosage during the first 30 days after first liver transplant (LT). METHODS: A total of 35 patients submitted to first LT between 2016 and 2018 were retrospectively enrolled: 16 received LCP-TAC, while 19 received TAC-PR as de novo immunosuppression. Patients were analyzed for daily dosage and trough levels at postoperative days (PODs) 3, 7, 15, and 30. RESULTS: The initial dose of tacrolimus did not differ between LCP-TAC and TAC-PR (mean, 5.19 [SD, 1.72] mg/d vs mean, 5.26 [SD, 1.91] mg/d, P = .90). On PODs 7, 15, and 30 the daily dosage was statistically lower for LCP-TAC compared with TAC-PR (mean, 5.44 [SD, 2.06] mg/d vs mean, 7.68 [SD, 2.91] mg/d, P = .01; mean, 5.33 [SD, 2.23] mg/d vs mean, 8.82 [SD, 2.35] mg/d, P < .001; and mean, 5.38 [SD, 2.50] mg/d vs mean, 9.81 [SD, 3.78] mg/d, P < .001, respectively). The therapeutic trough levels were significantly higher for LCP-TAC on POD 3 (mean, 5.05 [SD, 3.58] ng/mL vs mean, 2.42 [SD, 2.75] ng/mL, P = .03) and POD 5 (mean, 7.35 [SD, 5.12] ng/mL vs mean, 4.17 [SD, 2.05] ng/mL, P = .04), while no differences were found on PODs 7, 15, and 30.The percentage of patients on POD 3 achieving a trough level higher than 6 ng/mL was higher for LCP-TAC than TAC-PR (40% vs 13%, P = .05). CONCLUSIONS: LCP-TAC after LT is safe and might enhance bioavailability, reducing the amount of drug necessary to achieve therapeutic trough levels compared with TAC-PR.


Assuntos
Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Transplante de Fígado , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Adulto , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Feminino , Humanos , Imunossupressão/métodos , Imunossupressores/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/sangue
6.
Acta Cir Bras ; 34(8): e201900806, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618406

RESUMO

PURPOSE: To assess Cyclosporine A (CsA) therapy at an intraperitoneal dose of 15 mg.kg -1 in a rodent model of non-septic renal ischemia. METHODS: Twenty male Wistar rats were randomized to receive CsA therapy or none therapy before undergoing 30 minutes of renal ischemia followed by reperfusion. Additionally, 10 rats were randomized to undergo the same surgical procedure of the aforementioned animals with neither ischemia nor CsA therapy. Twelve hours after kidney ischemia, the left kidneys were evaluated for histological injury according to Park's criteria. Serum creatinine (Cr), urea nitrogen (Ur) and sodium levels were obtained at different times of the experimental protocol. RESULTS: Rodents in the CsA group showed negative results (p<0.05) in serum variables (Cr: 0.41±0.05mg/dL vs . 4.17±1.25mg/dL; Ur: 40.90±3.98mg/dL vs . 187.70±22.93mg/dL) even the non CsA or control group (Cr: 0.35±0.07mg/dL vs . 3.80±1.20mg/dL; Ur: 40.10±4.70mg/dL vs . 184.50±49.80mg/dL). The negative results were also verified in histological evaluation, CsA group had 50% in the very severe grade of lesion, 10% in the severe and 40% in the moderate to severe whereas the control group had 90% in the very severe grade. CONCLUSION: CsA was incapable of preventing the deleterious effects of ischemia-reperfusion injury in rat kidneys.


Assuntos
Ciclosporina/farmacologia , Imunossupressores/farmacocinética , Rim/irrigação sanguínea , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Creatinina/sangue , Modelos Animais de Doenças , Isquemia/prevenção & controle , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia , Sódio/sangue , Ureia/sangue
7.
Expert Opin Drug Metab Toxicol ; 15(10): 803-811, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31595800

RESUMO

Introduction: Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplantation (HSCT); therefore, the prevention of GVHD is important for a successful treatment. Tacrolimus (Tac), a calcineurin inhibitor, has been widely used for the prophylaxis of GVHD in HSCT recipients. Areas covered: This review introduces phase II/III of clinical trials related with Tac's roles in the prevention of GVHD in HSCT. Furthermore, we discuss the normal ranges of Tac concentrations, pharmacogenetics, and drug interactions of Tac, as well as its side effects in adult HSCT recipients. Expert opinion: A series of studies has established the efficacy and safety of Tac alone or in combination with other agents in HSCT. However, successful administration of Tac is complicated by its narrow therapeutic window, inter-patient pharmacokinetic variability, and a spectrum of undesirable side effects. It is necessary to maintain concentrations of Tac within the desired ranges for GVHD prophylaxis. Moreover, various factors contribute to significant variability in Tac pharmacokinetics, including drug interactions and genomic variation.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Tacrolimo/administração & dosagem , Adulto , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/farmacocinética , Interações de Medicamentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Farmacogenética , Tacrolimo/efeitos adversos , Tacrolimo/farmacocinética
8.
Transplant Proc ; 51(8): 2624-2628, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31563242

RESUMO

INTRODUCTION: Mycophenolate mofetil has improved long-term outcomes of kidney transplantation. However, the impact of mycophenolic acid (MPA) trough level on the development of de novo donor-specific anti-HLA antibody (DSA) is unclear. We examined the relation between MPA trough level and de novo DSA development. METHOD: We retrospectively studied 617 kidney recipients whose MPA trough level and de novo DSA data were available. All patients underwent primary kidney transplant from living donors from 2008 to 2014, and were chronically treated with a calcineurin inhibitor, mycophenolate mofetil, and +/- steroids. They were equally divided into 4 groups according to the mean trough level of MPA (mMPA) at 1 year post-transplantation: Group 1, mMPA < 2.14 ng/mL (n = 152); Group 2, mMPA 2.14-2.83 ng/mL (n = 157); Group 3, mMPA 2.83-3.57 ng/mL (n = 153); and Group 4, mMPA ≥ 3.57 ng/mL (n = 155). The groups were compared by incidence rate of de novo DSA, graft survival rate, and renal function. RESULTS: The incidence rates of de novo DSA were 33.3% in Group 1, 23.7% in Group 2, 22.9% in Group 3, and 30.3% in Group 4 (P = .158). Although there was no significant difference in graft survival rates, a significant difference of renal functions was noted: the higher the renal function, the lower the MPA trough level. CONCLUSION: The mMPA trough level at 1 year post-transplantation was not statistically associated with the incidence rate of de novo DSA after kidney transplantation.


Assuntos
Soro Antilinfocitário/efeitos dos fármacos , Rejeição de Enxerto/prevenção & controle , Imunossupressores/farmacocinética , Transplante de Rim/efeitos adversos , Ácido Micofenólico/farmacocinética , Adulto , Anticorpos/imunologia , Soro Antilinfocitário/imunologia , Inibidores de Calcineurina/administração & dosagem , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Humanos , Transplante de Rim/métodos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
9.
Molecules ; 24(19)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554326

RESUMO

With the increase in the number of medicines patients have to take, there has been a rapid rise of fixed-dose combinations (FDCs) in the last two decades. Prior to FDC development, pharmacokinetic properties of active pharmaceutical ingredients (APIs) have to be evaluated, as well as methods for their determination developed. So as to increase patient compliance in inflammatory bowel disease, three novel FDCs of thiopurine immunosuppressants and folic acid are proposed; physico-chemical and pharmacokinetic properties such as hydrophobicity, lipophilicity and plasma protein binding of all APIs are evaluated. Moreover, experimental results of different properties are compared to those computed by various on-line prediction platforms so as to evaluate the viability of the in silico approach. A simultaneous method for their determination is developed, optimized, validated and applied to commercial tablet formulations. The method has shown to be fast, selective, accurate and precise, showing potential for reliable determination of API content in proposed FDCs during its development.


Assuntos
Cromatografia , Ácido Fólico/farmacocinética , Imunossupressores/farmacocinética , Fenômenos Químicos , Cromatografia Líquida de Alta Pressão , Ácido Fólico/administração & dosagem , Ácido Fólico/química , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/química , Estrutura Molecular
10.
Transplant Proc ; 51(8): 2643-2647, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31477420

RESUMO

BACKGROUND: The stable immunosuppressant level at the early period after kidney transplantation (KT) is one of the most important factors for the prognosis of KT. However, the extent of immunosuppression varies according to the policies of each KT center. We investigated the relationship between the clinical outcome and tacrolimus trough level (TTL) at the early post-transplant period. MATERIALS AND METHODS: We retrospectively analyzed medical records of patients who underwent KT between July 2007 and June 2016. We investigated TTLs at 3 months after KT. We evaluated the incidence of biopsy-proven acute rejection (BPAR), cytomegalovirus infection, and graft survival according to the TTLs. RESULTS: A total of 426 patients who received KT during the study period were enrolled. The mean age of KT recipients was 46.3 ± 11.5 years, and 55.5% of patients were men. The incidence of BPAR within 1 year after KT was significantly higher when TTLs at 3 months were less than 4.0 ng/mL (P = .020). Death-censored graft survival rates were significantly lower in KT recipients with BPAR and TTL less than 4.0 ng/mL (P < .001, P < .001, respectively). In multivariate analysis, BPAR and TTL less than 4.0 ng/mL at 3 months after KT were independent risk factors for graft failure. CONCLUSION: BPAR and TTL less than 4.0 ng/mL at 3 months after KT are important risk factors for allograft failure. Therefore, TTL should be kept at least 4.0 ng/mL or more at 3 months after KT to reduce the incidence of BPAR within 1 year after KT.


Assuntos
Rejeição de Enxerto/epidemiologia , Imunossupressão/métodos , Imunossupressores/farmacocinética , Transplante de Rim , Tacrolimo/farmacocinética , Adulto , Feminino , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Transplante Homólogo
11.
Transplant Proc ; 51(8): 2629-2632, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31471014

RESUMO

BACKGROUND: Mycophenolic acid (MPA) is one of the main immunosuppressive regimens used after kidney transplantation (KT). The less expensive, generic form of mycophenolate mofetil (MMF) (Immucept®) is recently available in Thailand. Comparisons of the pharmacokinetic profiles between the original and generic forms of MMF among post-KT patients are limited. METHODS: This prospective cohort study recruited KT patients receiving stable doses of MMF 1000 mg daily along with tacrolimus and steroids. All participants were prescribed CellCept® 500 mg every 12 hours for at least 2 weeks before measuring the MPA area under the curve from 0 to 12 hours (AUC0-12). CellCept® was switched to Immucept® 500 mg every 12 hours for 2 weeks and MPA AUC0-12 was remeasured. RESULTS: Twenty patients with a median follow-up time of 35.4 (11.13-198.83) months were enrolled. Mean MPA AUC0-12 of Immucept® was higher than CellCept® without statistical significance (48.27 ± 2.31 µg⋅hr/mL vs 42.19±15.20 µg⋅hr/mL; P value = .59). No difference was revealed regarding the minimum measured concentration, maximum measured concentration, and time point with maximum concentration between both drugs. While on CellCept®, 5 patients (25%) had an MPA AUC0-12 < 30.0 µg⋅hr/mL, but 3 patients (15%) had MPA AUC0-12 < 30.0 µg⋅hr/mL when receiving Immucept®. However, 3 (15%) and 6 (30%) patients had MPA AUC0-12 > 60.0 µg⋅hr./mL when treated with CellCept® and Immucept®, respectively. CONCLUSION: Generic MMF exhibited a comparable pharmacodynamic profile as the original formulation. MPA AUC0-12 was more than 30.0 µg⋅hr/mL among most patients receiving MMF 1000 mg/day.


Assuntos
Medicamentos Genéricos/farmacocinética , Imunossupressores/farmacocinética , Transplante de Rim , Ácido Micofenólico/farmacocinética , Adulto , Área Sob a Curva , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Prospectivos , Esteroides/administração & dosagem , Tacrolimo/administração & dosagem , Tailândia , Resultado do Tratamento
12.
Int Immunopharmacol ; 75: 105772, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376625

RESUMO

Everolimus (EVR) is often administered with cyclosporine A (CsA), according to an established protocol. Although the administration protocol of EVR with tacrolimus (TAC) has not been established, it has been clinically demonstrated that a higher dose of EVR is necessary when used in combination with TAC than with CsA. In this study, we aimed to determine the optimal dose of EVR administered with TAC to maintain a similar EVR level in the blood to that observed when EVR is administered with CsA. Between June 2009 and January 2016, 22 patients who underwent living donor kidney transplantation were enrolled in this study. Among them, 12 patients were administered steroids, basiliximab, CsA, and EVR (CsA + EVR group) and 10 were administered steroids, basiliximab, TAC, and EVR (TAC + EVR group). Blood samples were collected at different time points from patients in both CsA + EVR and TAC + EVR groups, after drug administration. The trough EVR level in both groups was maintained within 3-8 ng/mL during the perioperative period. The optimal EVR doses for both groups were estimated by using a population pharmacokinetic analysis. Overall, the optimal dose of EVR for the TAC + EVR group was 3.59-fold higher than that for the CsA + EVR group to maintain a similar trough level to that of the latter group. Thus, administration of a higher EVR dose is recommended when provided in combination with TAC than with CsA to prevent adverse events caused by under immunosuppression, that could lead to acute kidney rejection.


Assuntos
Everolimo/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim , Doadores Vivos , Tacrolimo/administração & dosagem , Adulto , Basiliximab/administração & dosagem , Ciclosporina/administração & dosagem , Ciclosporina/sangue , Ciclosporina/farmacocinética , Everolimo/sangue , Everolimo/farmacocinética , Feminino , Humanos , Imunossupressores/sangue , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Esteroides/administração & dosagem , Tacrolimo/sangue , Tacrolimo/farmacocinética
13.
Clin Drug Investig ; 39(12): 1175-1184, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31444778

RESUMO

BACKGROUND AND OBJECTIVES: Mycophenolic acid (MPA) is commonly used following renal transplant. Saliva MPA concentrations may reflect the pharmacologically active form of MPA in plasma. Therapeutic drug monitoring using saliva is convenient and non-invasive. This study examined the correlation between total and free plasma and saliva MPA concentrations following enteric-coated mycophenolate sodium (EC-MS) administration in renal transplant recipients. METHODS: Total and free plasma and saliva MPA concentrations were measured simultaneously in 20 adult renal transplant recipients 1-2 months' post-transplant. Thirteen samples were taken pre-dose and at specified time points up until 12 h post-dose. RESULTS: When considering all time points, correlation between total plasma and saliva MPA was r2 = 0.51 and between free plasma and saliva MPA concentrations r2 = 0.41. The correlation between total plasma MPA area under the concentration-time curve (AUC) or free plasma AUC and saliva MPA AUC was r2 = 0.25 and r2 = 0.13, respectively. The correlation between total plasma MPA AUC and total plasma MPA trough (C0) concentrations was r2 = 0.51, and between total plasma MPA AUC and saliva MPA trough concentrations, r2 = 0.03. CONCLUSIONS: Measurement of MPA concentration in saliva cannot currently replace plasma measurement for therapeutic drug monitoring of MPA following EC-MS administration. Additional studies are required to examine the relationship between MPA saliva concentrations and patient outcomes.


Assuntos
Imunossupressores/farmacocinética , Transplante de Rim , Ácido Micofenólico/farmacocinética , Saliva/metabolismo , Adulto , Idoso , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem
14.
Biomater Sci ; 7(9): 3729-3740, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31403142

RESUMO

Targeted delivery of immunosuppressants to allografts can increase the concentrations of drugs in pathological tissues, improve therapeutic effects and reduce unfavorable side effects. Therefore, we synthesized FK506-loaded microbubbles (FK506-MBs) for site-specific release of FK506 into transplanted hearts by the ultrasound-targeted microbubble destruction (UTMD) technique. The average particle size of FK506-MBs was 1.65 ± 0.32 µm and they had high drug loading and encapsulation efficiency. The in vivo drug concentration in transplanted hearts that were treated with FK506-MBs plus UTMD was about 1.64-fold higher than that in grafts that received free FK506 at the same dosage. The degree of graft rejection in the FK506-MB plus UTMD group was lower than those of other groups. Both infiltration of T cells and secretion of inflammatory cytokines were significantly reduced in the FK506-MB plus UTMD group. More importantly, the mean survival time of the grafts was significantly longer (16.00 ± 0.89 day) than those of the PBS group (6.66 ± 1.36 day) and the FK506 group (12.83 ± 1.17 day). In addition, we also found that the concentration of FK506 in whole blood was lower in the FK506-MB plus UTMD group than that in the FK506 group, which would be beneficial for reducing the side effects. Hence, our results showed that combining FK506-MBs with UTMD was an effective strategy to deliver FK506 to transplanted hearts, which can increase the local drug concentration and enhance its efficacy on rejection. Ultrasound-targeted drug release is safe and radiation-free, with great potential for clinical transformation, and could also be extended to the treatment of other graft rejection cases, such as liver transplantation, kidney transplantation and so on.


Assuntos
Portadores de Fármacos/química , Rejeição de Enxerto/tratamento farmacológico , Transplante de Coração , Imunossupressores/farmacocinética , Miocárdio/metabolismo , Tacrolimo/farmacocinética , Animais , Liberação Controlada de Fármacos , Estudos de Viabilidade , Imunossupressores/administração & dosagem , Masculino , Microbolhas , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos , Tacrolimo/administração & dosagem , Ultrassonografia
15.
J Vet Intern Med ; 33(5): 2020-2028, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31423655

RESUMO

BACKGROUND: Mycophenolate mofetil (MMF) is an immunosuppressant used in human and veterinary medicine. Little pharmacokinetic and pharmacodynamic information on MMF is available in cats. OBJECTIVE: To evaluate the plasma disposition of mycophenolic acid (MPA) and assess its effect on total peripheral blood mononuclear cells and CD4+ /CD8+ ratios after PO administration of MMF. ANIMALS: Healthy cats (n = 10). METHODS: Mycophenolate mofetil was administered at a dosage of 10 mg/kg q12h (n = 3), 15 mg/kg q12h (n = 3), and 15 mg/kg q8h (n = 4) for 7 days. Concentrations of MPA and derivatives were determined using ultra-high-performance liquid chromatography. Flow cytometry was used to assess CD4+ /CD8+ T-cell ratios. RESULTS: All cats biotransformed MMF into MPA. Half of the cats (5/10) had adverse effects within 1 week of MMF administration. Area under the curve limit of quantification (AUC0-LOQh ) of MPA ranged from 1.27 to 2.03 hours·µg/mL and from 1.77 to 8.54 hours·µg/mL after the first and last PO dose of 10 mg/kg. The AUC0-loqh of MPA ranged from 2.18 to 31 hours·µg/mL after the first dose of 15 mg/kg of MMF. Before the first dose of MMF, the average total number of PBMC ranged from 1.2 to 9.3 million/mL. At the last dose of MMF, the average total number of PBMC ranged from 3 to 5 million/mL. CONCLUSION: Mycophenolic acid was detected in all cats. The dose 10 mg/kg given q12h for 1 week was tolerated (n = 3). The efficacy of MMF as an immunosuppressant and long-term safety in cats of this dosage regimen is unknown.


Assuntos
Gatos , Imunossupressores/farmacocinética , Leucócitos Mononucleares/efeitos dos fármacos , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Ácido Micofenólico/efeitos adversos
16.
Int J Clin Pharmacol Ther ; 57(10): 506-519, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31397274

RESUMO

OBJECTIVE: Mycophenolate mofetil (MMF) is widely used as an immunosuppressant for the prophylaxis of acute organ rejection in recipients of solid organ transplants. MATERIALS AND METHODS: We have compared, in healthy subjects, the pharmacokinetics of mycophenolic acid when MMF was administered in the form of the innovator product CellCept (F. Hoffmann-La Roche Ltd.) or one of three commercially available generics, Renodapt (Biocon Ltd.), Mycept (Panacea Biotec), or Cellmune (Cipla Ltd.). The study was powered to detect a 20% difference in mean formulation performance measures, but not to formally evaluate bioequivalence. Geometric mean ratios of maximum concentrations (Cmax) and areas under plasma concentration-time curves were calculated. RESULTS: Comparing generics against each other, the differences in point estimates of the geometric mean ratios of Cmax of two of the comparisons were either borderline within (Renodapt/Cellmune) or clearly outside (Mycept/Cellmune) a region of 80 - 125% around the reference mean, indicating that bioequivalence between these generics may be difficult to show. CONCLUSION: Physicians in the field of transplantation should be aware of the potential risk of altering the therapeutic outcome when switching from one preparation of MMF to another. ClinicalTrials.gov identifier: NCT02981290.


Assuntos
Medicamentos Genéricos/farmacocinética , Imunossupressores/farmacocinética , Ácido Micofenólico/farmacocinética , Equivalência Terapêutica , Estudos Cross-Over , Rejeição de Enxerto , Humanos
17.
Curr Drug Metab ; 20(8): 682-694, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31385766

RESUMO

BACKGROUND: Cyclosporine is used as an immunosuppressive agent in kidney transplantation. It has a narrow therapeutic window. Cyclosporine is predominantly metabolized by CYP3A4 and CYP3A5. The most common Single Nucleotide Polymorphisms (SNPs) affecting cyclosporine metabolism (CYP3A4*1B, CYP3A4*1G, CYP3A4*22 and CYP3A5*3) were investigated among Jordanian kidney transplanted patients to find out the genotypes and allele frequencies of these SNPs. Additionally, this study investigated whether genotypes of CYP3A4 and CYP3A5 affect C2 blood levels, dosing of cyclosporine and the prevalence of acute rejection. METHODS: Blood samples of 109 adult patients taking cyclosporine as their primary immunosuppressant for kidney transplantation were collected from the Prince Hamzah Hospital, Amman, Jordan. Patients' first C2 blood levels and their first two given doses were collected. Patients were genotyped for the four SNPs using Polymerase Chain Reaction- restriction Fragment Length Polymorphism (PCR-RFLP) assay method. RESULTS: Allele frequencies among Jordanian patients for CYP3A4*1B, CYP3A4*1G, CYP3A4*22 and CYP3A5*3 were 0.037, 0.399, 0.037 and 0.271, respectively. There was a significant association between CYP3A4*22 and mean difference in the second and first given doses (P=0.034). There was a big difference between CYP3A4*22 and the mean of the first C2 blood levels (P=0.063). CONCLUSION: There was a strong association between CYP3A4*22 and the mean difference between the second and first given doses. There was a trend of significant difference between the mean of the first C2 blood levels among heterozygous CYP3A4*22 patients. Pharmacogenomics may hold promise in assisting the prediction of the best cyclosporine dose and C2 blood level among Jordanian kidney transplant patients.


Assuntos
Ciclosporina/sangue , Citocromo P-450 CYP3A/genética , Imunossupressores/sangue , Transplante de Rim , Adolescente , Adulto , Idoso , Ciclosporina/farmacocinética , Ciclosporina/uso terapêutico , Feminino , Genótipo , Humanos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Jordânia , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Adulto Jovem
18.
AAPS PharmSciTech ; 20(6): 247, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286321

RESUMO

We aim to describe the influence of principal ingredients of Wuzhi capsule, schisandrin A (SIA) and schisantherin A (STA), on the pharmacokinetics of cyclosporin A (CsA) and to quantify the herb-drug interactions (HDIs) between SIA, STA, and CsA. CsA is a first-line immunosuppressant for anti-rejection therapy after solid organ transplantation, while narrow therapeutic window associated with strong hepatotoxicity largely limited its use. Wuzhi capsule, a liver-protective drug, was approved for coadministration with CsA to reduce the hepatotoxicity. There are few studies exploring HDIs of CsA when coadministered with Wuzhi capsule. The essential adjusted physicochemical data and pharmacokinetic parameters of SIA, STA, and CsA were collected. Then physiologically based pharmacokinetic (PBPK) models of SIA, STA, and CsA were built and verified in healthy subjects using Simcyp respectively. The refined PBPK models were used to estimate potential HDIs between CsA and SIA, STA. The simulated plasma concentration-time curves of CsA, SIA, and STA were in good accordance with the observed profiles respectively. CsA pharmacokinetics were improved after coadministration. After a single dose and multiple doses, the area under the plasma concentration-time curve (AUC) of CsA was increased by 47% and 226% when coadministered with STA, respectively, and by 8% and 36% when coadministered with SIA, respectively. PBPK models sufficiently described the pharmacokinetics of CsA, SIA, and STA. Compared with SIA, STA inhibited CsA metabolism to a greater extent. Our result revealed the dose of CsA can be reduced to maintain similar profile when used concomitantly with Wuzhi capsule.


Assuntos
Ciclo-Octanos/administração & dosagem , Ciclosporina/farmacocinética , Dioxóis/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Imunossupressores/farmacocinética , Lignanas/administração & dosagem , Compostos Policíclicos/administração & dosagem , Adulto , Ciclo-Octanos/química , Ciclosporina/administração & dosagem , Dioxóis/química , Interações Ervas-Drogas , Humanos , Imunossupressores/administração & dosagem , Lignanas/química , Masculino , Compostos Policíclicos/química
19.
Transplant Proc ; 51(6): 1754-1757, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31255354

RESUMO

BACKGROUND: Although high tacrolimus (FK) intrapatient variability (IPV) was shown to be associated with poor graft outcome in kidney transplant recipients (KTRs), it is uncertain whether there is any association between the CYP3A5 genotype and IPV of FK concentrations. Instead of trough level, we use calculated abbreviated AUC0-12 to investigate the impact of CYP3A5 genetic polymorphism on IPV of FK pharmacokinetics. METHODS: We conducted a retrospective, single-center study of 86 adult Chinese KTRs with known CYP3A5 genotype. Coefficient of variation (CV) was used for the quantification of FK IPV. CV of dose-normalized FK AUC0-12 was calculated and was compared between the CYP3A5 expresser group and nonexpresser group. RESULTS: Forty-one patients (47.7%) were classified as CYP3A5 expressers while 45 were nonexpressers. No significant differences in the baseline characteristics were found between expressers and nonexpressers. CYP3A5 expressers required 1.8 times higher FK dose compared with the nonexpressers. There was no significant difference in the FK CV between CYP3A5 expressers (18.2 ± 7.5%) and nonexpressers (16.7 ± 5.7%) (P = .31). CONCLUSION: The IPV of FK exposure was not associated with CYP3A5 genotype in stable KTRs. Further studies should focus on other factors such as medication nonadherence, which may explain FK IPV.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , Transplante de Rim , Variantes Farmacogenômicos/genética , Tacrolimo/farmacocinética , Adulto , Grupo com Ancestrais do Continente Asiático , Feminino , Genótipo , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Tacrolimo/uso terapêutico , Transplantados
20.
Orv Hetil ; 160(30): 1178-1183, 2019 Jul.
Artigo em Húngaro | MEDLINE | ID: mdl-31327249

RESUMO

Tacrolimus is an important part of immunosuppressive therapy after solid organ transplantation. The therapeutic range of the drug from the calcineurin inhibitor group is narrow. Adjustment of the blood concentration can be very complicated but to be able to avoid the occurrence of side effects or ineffective immunosuppression it is inevitable. This article summarizes the properties of tacrolimus pharmacokinetics, pharmacogenetics and pharmacodynamics. We will focus on individual variations of cytochrome enzymes. In the following part, a new method for screening high risk patients will be introduced. We will present the publications of the determination of the concentration/dose (C/D) ratio. By determining the C/D ratio, researchers identify fast and slow metabolizing patient groups. Fast metabolizers require higher doses in general and the occurrence of complications is also more frequent in this group. Long-term results are lagging behind the slow metabolizing group. The long-term results of renal transplantation nowadays contribute to the postoperative period and the later years rather than the surgery itself. It includes the proper management of previous illnesses (e.g., hypertension, diabetes, endocrinological problems), detection of complications (e.g., infections, malignancies), and the precise regulation of immunosuppressive therapy. Orv Hetil. 2019; 160(30): 1178-1183.


Assuntos
Imunossupressores/uso terapêutico , Transplante de Rim , Rim/efeitos dos fármacos , Tacrolimo/farmacologia , Tacrolimo/farmacocinética , Inibidores de Calcineurina/farmacocinética , Sobrevivência de Enxerto , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Farmacogenética , Tacrolimo/uso terapêutico , Resultado do Tratamento
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