In vitro dissolution kinetic for mycophenolic acid derivatives tablets

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.

Impact of UGT1A9 polymorphism on mycophenolic acid pharmacokinetic parameters in stable renal transplant patients

There are wide individual differences in pharmacokinetic parameters of mycophenolate mofetil [MMF] among transplanted patients. Some studies have shown that single nucleotide polymorphisms [SNPs] of the Uridine Diphosphate Glucuronosyl Transferase1A9 [UGT1A9] are responsible for these differences in early days after transplantation. Therefore it was decided to evaluate the influence of UGT polymorphism on MMF pharmacokinetics among stable Iranian transplant patients. This was a cross sectional study from March 2008 through December 2008 in Imam Khomeini Hospital affiliated to the Tehran University of Medical Sciences in Iran. Blood samples were taken from 40 de novo stable Iranian renal transplant patients taking 2 g MMF daily with Sr[Cr]

A pilot study on area under curve of mycophenolic acid as a guide for its optimal use in renal transplant recipients.

Background & objectives: The immunosuppressants administered to renal transplant subjects are usually monitored therapeutically to prevent graft rejection and drug toxicity. Mycophenolic acid (MPA) is an immunosuppressant. The present prospective study was undertaken to establish the utility of plasma level monitoring of MPA and to correlate it with clinical outcomes in renal transplant receipients. Methods: MPA plasma level at 2, 4 and 9 h and the area under concentration-time curve (AUC) were estimated using high performance liquid chromatography in 24 renal transplant recipients receiving immunosuppressant MPA plus tacrolimus and steroid. Results: There was wide inter-individual variation in MPA plasma level and the AUC. The incidences of gastrointestinal adverse drug events (diarrhoea and acidity) were significantly more in the high MPA AUC patients. Though biopsy proven acute rejection was not found, of the six subjects with lower MPA AUC (<30 mg.h/l), three were clinically diagnosed to develop tacrolimus nephrotoxicity. The Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI) scores represented better health related quality of life in lower MPA AUC than in the higher MPA AUC (>60 mg.h/l). Interpretation & conclusions: The present findings suggest the MPA AUC of 30 - 60 mg.h/l in the maintenance stage of renal transplant patients to have optimum clinical benefit and relegated adverse events profile indicating the usefulness of AUC of MPA with limited sampling strategy in optimizing its use.

Estudio de biodisponibilidad relativa entre dos formulaciones orales de micofenolato mofetilo en voluntarios sanos / Relative bioavailability study of two oral formulations of mycophenolate mofetil in healthy volunteers

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.

Avaliação da biodisponibilidade de uma nova formulação de micofenolato mofetil e de um método para sua monitorização / Assessment of the bioaviability of a new micophenolate mofetil formulation and a method for therapeutic monitoring

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...

Co-interferências da farmacocinética dos inibidores de calcineurina em associação com micofenolato mofetil em pacientes transplantados renais / Interference of calcineurin inhibitors on the pharmakocinetics of mycophenolic acid in renal transplantation

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...