RESUMO
OBJECTIVE: It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression. METHODS: In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. RESULTS: The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (nâ =â 86) and control (nâ =â 168) patients [geometric means ratios (GMR)â =â 0.99, 95% confidence interval (CI)â =â 0.92-1.06 and GMRâ =â 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR)â =â 0.94, 0.49-1.84 and RRâ =â 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed nâ =â 23, control nâ =â 45), if cotreated with cyclosporine (nâ =â 17 vs. nâ =â 26) or with tacrolimus (nâ =â 8 vs. nâ =â 17). CONCLUSIONS: In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state.
Assuntos
Taxa de Filtração Glomerular , Transplante de Rim , Transportador 1 de Ânion Orgânico Específico do Fígado , Ácido Micofenólico , Humanos , Transplante de Rim/efeitos adversos , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/farmacocinética , Masculino , Feminino , Pessoa de Meia-Idade , Taxa de Filtração Glomerular/efeitos dos fármacos , Adulto , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Alelos , Imunossupressores/efeitos adversos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Coortes , Rejeição de Enxerto/genética , Rejeição de Enxerto/prevenção & controleRESUMO
The recommended immunosuppressive treatment after kidney transplantation consists of tacrolimus, mycophenolate mofetil, and low-dose corticosteroids. Drug concentrations are monitored using therapeutic drug monitoring (TDM), which does not necessarily correlate with pharmacodynamic activity. To find the balance between optimal efficacy and minimal toxicity, it might be more informative to monitor patients' immunological status rather than drug concentrations. We selected a panel of T-cell-based immune assays, which were used for immunomonitoring of 14 stable kidney transplantation patients. Whole blood was incubated with a T-cell stimulus, after which T-cell proliferation, T-cell activation marker expression and cytokine production were measured to study residual immune activity in vitro (before drug intake; drug added to the incubation) and ex vivo (after drug intake). T-cell proliferation was completely suppressed in all patients over the full day, while IL-2, IFN-γ, CD71, and CD154 showed fluctuations over the day with a strong inhibition (75%-25%) at 2 h post-dose. The level of inhibition was variable between patients and could not be related to pharmacokinetic parameters or the presence of regulatory or senescence immune cells. Moreover, the level of inhibition did not correlate with the in vitro tacrolimus drug effect as studied by incubating pre-dose blood samples with additional tacrolimus. Overall, IL-2, IFN-γ, CD71, and CD154 seem to be good markers to monitor residual immune activity of transplantation patients. To evaluate the correlation between these pharmacodynamic biomarkers and clinical outcome, prospective observational studies are needed.
Assuntos
Proliferação de Células , Monitoramento de Medicamentos , Imunossupressores , Transplante de Rim , Ativação Linfocitária , Linfócitos T , Tacrolimo , Humanos , Masculino , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Pessoa de Meia-Idade , Feminino , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Adulto , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Tacrolimo/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Idoso , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/farmacocinética , Interferon gama/metabolismoRESUMO
On June 6, 2022, the FDA expanded the indications for mycophenolate mofetil (MMF) to include the prophylaxis of organ rejection in combination with other immunosuppressants in pediatric recipients of allogeneic heart or liver transplants aged 3 months and older. The approved oral dosing regimen for these patients was a starting dose of 600 mg/m2 with titration up to a maximum of 900 mg/m2 twice daily. Data to support efficacy in pediatric patients were derived from established pharmacokinetic (PK) relationships across approved populations, a PK study in pediatric liver transplant recipients, and information from the Scientific Registry of Transplant Recipients database. Information supporting safety was based on comparing mycophenolic acid (MPA) exposure with that in pediatric kidney transplant recipients, the published literature, and post-marketing safety reports. Efficacy in pediatric patients was established based on extrapolation of efficacy from studies in adult liver, adult heart, and pediatric kidney transplant populations, and similarity in MPA exposure between pediatric and adult patients. Review of the data supported an oral dosing regimen for pediatric heart transplant and liver transplant recipients consisting of a starting dose of 600 mg/m2 up to a maximum of 900 mg/m2 b.i.d. A dosage range for MMF is recommended recognizing that the MMF dose may be modified in clinical practice for myriad factors. The dosage recommendations in the labeling for pediatric liver and pediatric heart transplant patients are intended to permit individualized dosing based on clinical assessment of these factors.
Assuntos
Aprovação de Drogas , Rejeição de Enxerto , Transplante de Coração , Imunossupressores , Transplante de Fígado , Ácido Micofenólico , Humanos , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Transplante de Coração/efeitos adversos , Criança , Imunossupressores/farmacocinética , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Estados Unidos , Pré-Escolar , Lactente , Adolescente , United States Food and Drug AdministrationRESUMO
The clinical impact of individual dose adjustment of mycophenolate mofetil is still debated, due to conflicting results from randomized clinical trials. This retrospective study aimed to compare 3-year rejection-free survival and adverse effects between adult kidney transplant recipients (KTRs) with or without mycophenolate mofetil model-informed precision dosing (MIPD). MIPD is defined here as mycophenolic acid area under the curve (AUC0-12h) estimation using a limited sampling strategy, pharmacokinetic models and Bayesian estimators; dose recommendation to reach AUC0-12h = 45 mg.h/L; using a widely used online expert system. The study, nested in two multicenter prospective cohort studies, focused on patients who received a mycophenolate drug and were followed up for 1-3 years. Mycophenolate mofetil MIPD was prescribed as per local practice, on a regular basis, when deemed necessary, or not at all. The MIPD group included 341 KTRs and the control group 392. At 3 years, rejection-free survival was respectively 91.2% and 80.6% (P < 0.001) and the cumulative incidence of rejection 5.08% vs. 12.7% per patient × year (hazard ratio = 0.49 (0.34, 0.71), P < 0.001), corresponding to a 2.5-fold reduction. Significant association with rejection-free survival was confirmed in patients at low or high risk of rejection (P = 0.017 and 0.013) and in patients on tacrolimus, but not on cyclosporine (P < 0.001 and 0.205). The mycophenolate mofetil MIPD group had significantly more adverse effects, but most occurred before the first AUC0-12h, suggesting some may be the reason why MIPD was ordered.
Assuntos
Rejeição de Enxerto , Imunossupressores , Transplante de Rim , Ácido Micofenólico , Humanos , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Estudos Retrospectivos , Adulto , Teorema de Bayes , Área Sob a Curva , Estudos Prospectivos , Idoso , Modelos Biológicos , Sobrevivência de Enxerto/efeitos dos fármacos , TransplantadosRESUMO
AIM: The goal of this study was to evaluate whether topical administration of tacrolimus (TAC) and mycophenolic acid (MPA) at the transplant site enables vascularized composite allograft (VCA) survival with significant minimization of the dose and adverse effects of systemic TAC (STAC) immunosuppression. MATERIALS AND METHODS: Lewis (Lew) rats received orthotopic hind limb allotransplants from fully mismatched Brown Norway (BN) donors. Group 1 (Controls) received no treatment. Other groups were treated with STAC at a dose of 1 mg/kg/day for 7 days. On post-operative day (POD) 8, the STAC dose was dropped to 0.1 mg/kg/day for Group 2 and maintained at 1 mg/kg for Group 3. Group 4 received topical application of TAC and MPA on the transplanted (Tx) limb starting POD 8 without STAC. Group 5 received topical TAC and MPA on the contralateral non-Tx limb and Group 6 received topical TAC and MPA on the Tx limb starting POD 8 along with low dose STAC (0.1 mg/kg/day). Treatment was continued until the study end point was reached, defined as either grade 3 rejection or allograft survival exceeding 100 days. .We conducted sequential LC-MS/MS measurements to assess TAC and MPA concentrations in both blood/plasma and allograft tissues. Additionally, we evaluated markers indicative of organ toxicity associated with STAC immunosuppression. RESULTS: Compared to controls, topical therapy with TAC+MPA significantly prolonged allograft survival beyond 100 daysat very low dose STAC (0.1 mg/kg/day) (Group 6). The histopathological assessment of the grafts was consistent with the clinical outcomes. .Drug levels in blood/plasma remained low or undetectable, while allograft tissues showed higher drug concentrations compared to contralateral limb tissues (P<0.05). . Urinary creatinine clearance remained within the normal range at 2.5 mL/min. CONCLUSION: Combination therapy with topical TAC and MPA synergizes with a very low dose, corticosteroid- free-STAC regimen and facilitates rejection-free, prolonged VCA survival without morbidity.
Assuntos
Administração Tópica , Sobrevivência de Enxerto , Imunossupressores , Ácido Micofenólico , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Tacrolimo , Animais , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/farmacocinética , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Sobrevivência de Enxerto/efeitos dos fármacos , Ratos , Masculino , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/imunologia , Terapia de Imunossupressão/métodos , Alotransplante de Tecidos Compostos Vascularizados/métodos , Sinergismo Farmacológico , Aloenxertos Compostos/efeitos dos fármacos , AloenxertosRESUMO
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
Mycophenolate mofetil (MMF) and mycophenolate sodium (MPS) are an ester and a salt of mycophenolic acid. They have different kinetic in vivo characteristics due to differences in molecular structures, physicochemical properties and formulations administered. In this study, dissolution profiles of reference products were tested in different media to evaluate the effect of pH, kinetic dissolution and the best statistical model that can be used to predict the release of both drugs. The drug release was determined by using a validated ultraviolet spectrophotometry method, λ 250 nm. The method showed to be selective, linear, precise and accurate for MMF in 0.1 M HCl and MPS in sodium phosphate buffer pH 6.8. Dissolution kinetics models of zero order, first order, Higuchi, Hixson-Crowell and Weibull were applied to data in order to select the best fit by linear regression. The regression parameters were estimated and the models were evaluated with the results of residuals and coefficient of determination. The residuals obtained from dissolution kinetics models were random, uncorrelated, and normally distributed with constant variance. The R² values (74.7% for MMF and 95.8% for MPS) demonstrated good ability of the Weibull regression to explain the variability and to predict the drugs' release.
Micofenolato de mofetila (MMF) e micofenolato sódico (MPS) são, respectivamente, éster e sal sódico do ácido micofenólico. Os fármacos possuem características farmacocinéticas distintas em função das diferenças na estrutura molecular, nas propriedades físico-químicas e nas formulações administradas. Neste trabalho, os perfis de dissolução dos medicamentos referências foram testados em diferentes meios de dissolução com o objetivo de avaliar o efeito da variação de pH, a cinética de dissolução e o modelo estatístico mais adequado para prever a dissolução dos fármacos. A liberação dos fármacos foi determinada com método validado por espectroscopia no ultravioleta, λ 250 nm. O método mostrou-se seletivo, linear, preciso e exato para dissolução de MMF em 0,1 M HCl e MPS em tampão fosfato pH 6,8. Os modelos cinéticos de dissolução de ordem zero, primeira ordem, Higuchi, Hixson-Crowell e Weibull foram aplicados com o objetivo de selecionar aquele com o melhor ajuste por regressão linear. Os parâmetros de regressão foram estimados e os ajustes dos modelos foram verificados pelos resíduos e coeficientes de determinação. Os resíduos obtidos foram aleatórios, independentes, apresentaram variância constante e seguiram a distribuição normal. Os valores de R² (74,7% para MMF e 95,8% para MPS) indicaram bom ajuste da regressão de Weibull para explicar a variabilidade e estimar a liberação dos fármacos.
Assuntos
Técnicas In Vitro/métodos , Cinética , Dissolução/classificação , Liberação Controlada de Fármacos , Ácido Micofenólico/farmacocinéticaRESUMO
Background: The bioequivalence of different formulations of a same pharmaceutical product must be tested empirically. Aim: To evaluate the relative bioavailability for an oralformulation of mycophenolate mofetil (MMF) (Linfonex) compared to the reference formulation (Cellcept) to determine the bioequivalence between both formulations. Material and Methods: A randomized, crossover, double-blind trial in 22 healthy male volunteers, who received a single oral dose of 1000 mg of Linfonex and Cellcept with a washout period of 10 days. Plasma levels of the drug were determined by high performance liquid chr ornatography. Plasma concentrations were plotted and maximum concentration, area under the plasma concentration versus time between 0 and 12 hours after administration and área under plasma concentration curve versus time after administration between 0 and infinity, were calculated for both products. Results: The active compound, mycophenolic acid, was similarly absorbed in both formulations. No statistically significant differences were found in calculated pharmacokinetic parameters between both formulations. Conclusions: Linfonex 500 mg is bioequivalent to Cellcept 500 mg.
Assuntos
Adulto , Humanos , Masculino , Imunossupressores/farmacocinética , Ácido Micofenólico/análogos & derivados , Administração Oral , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Método Duplo-Cego , Imunossupressores/administração & dosagem , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/farmacocinética , Equivalência TerapêuticaRESUMO
Micofenolato mofetil (MMF) é largamente utilizado em transplantes de órgãos sólidos. Com a expiração da patente internacional, novas formulações vêm sendo disponibilizadas. Para garantir a segurança e eficácia, a nova formulação deve ser bioequivalente à formulação de referência. Estudamos a biodisponibilidade relativa de uma nova formulação de MMF, em vinte e quatro pacientes transplantados renais adultos. Foram analisadas as farmacocinéticas após a administração da droga de referência e da nova formulação, em esquema cruzado...
Mycophenolate mofetil (MMF) is largely used in solid organ transplantation. With the expiration of the international patent new MMF formulations are competing for the market. For the safety of the patients the new formulations must prove its bioequivalence with the brand name drug. We studied whether the reference formulation can be safely switched for a generic MMF. Twenty-four adult, renal transplanted patients have PK analysis...
Assuntos
Ácido Micofenólico/farmacocinética , Disponibilidade Biológica , Monitoramento de Medicamentos , Técnicas Imunoenzimáticas , Transplante de Rim , Equivalência TerapêuticaRESUMO
O ácido micofenólico (MPA) é o metabólito ativo do micofenolato mofetil (MMF), um imunossupressor seletivo para linfócitos amplamente utilizado em transplantes. A exposição ao MPA na fase inicial pós-transplante renal está associada com menor incidência de rejeição aguda e com maior sobrevida do enxerto / Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), a selective lymphocyte anti-proliferative drug. It has been demonstrated that early adequate exposure to MPA is associated with less acute rejection and better long-term outcome in kidney transplantation. To the present, the recommended therapeutic range for MPA is an area under the concentration-time curve...