Absorption characteristics of EC-MPS--an enteric-coated formulation of mycophenolic sodium.
ABSTRACT Enteric-coated mycophenolate sodium is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying MPA release until the small intestine.
Two studies were undertaken to identify the absolute bioavailability and dose-proportionality of enteric-coated mycophenolate sodium in stable renal transplant patients receiving cyclosporine.
Study 1: The mean MPA AUC(0-t) was shown to be greater after MPA infusion than after oral enteric-coated mycophenolate sodium (42.1 vs. 28.9 microg x h/ml). Mean absolute bioavailability was 0.71 +/- 0.21 (SD). Study 2: The AUC(0-t) and C(max) for MPA were proportional to the dose of enteric-coated mycophenolate sodium, similarly mean AUC(0-infinity) and C(max) for MPA glucuronide were proportional to dose administered.
In patients receiving cyclosporine the absolute bioavailability of MPA provided by enteric-coated mycophenolate sodium is equivalent to that provided by mycophenolate mofetil when administered in combination with cyclosporine, and exhibits dose-proportionality. Enteric-coated mycophenolate sodium was well tolerated from 180 - 2,160 mg with no serious adverse events reported.
- SourceAvailable from: Michael Walsh[Show abstract] [Hide abstract]
ABSTRACT: Background The use of mycophenolate mofetil (MMF) in autoimmune disease is often limited by adverse effects. In this single-centre, open label, parallel design study, we investigated whether enteric-coated mycophenolate sodium (MS) is better tolerated and therefore more efficacious than MMF in primary systemic vasculitis (PSV) and systemic lupus erythematosus (SLE). Methods Forty patients with vasculitis or systemic lupus erythematosus (SLE) due to commence MMF for active disease or remission maintenance were randomized to receive either 1440 mg/day MS or 2000 mg/day MMF (18 PSV, 2 SLE per group) in addition to corticosteroids. Random allocation was performed by minimization for age, diagnosis and renal function using a computer algorithm. Twenty-five were treated for active disease (5 first-line therapy, 20 salvage therapy) and 15 for remission maintenance. The composite primary end point was treatment failure and/or drug intolerance over 12 months. Treatment failure was defined as failure to achieve remission by 6 months or disease relapse and treatment intolerance was defined as inability to tolerate and maintain the target dose of MS or MMF within 12 months. Results Forty patients were included in the analyses. MS was associated with a lower primary end point rate [hazard ratio (HR) 0.37; 95% CI 0.17–0.80; P = 0.012] (11/20, 55% patients) compared with MMF (17/20, 85% patients). Treatment failure alone was less common in the MS group (HR 0.28; 95% CI 0.095–0.82; P = 0.020), although drug intolerance did not differ between groups (HR 0.53; 95% CI 0.20–1.42; P = 0.21). Despite randomization, patients in the MMF group may have had a higher baseline risk for treatment failure; more MMF patients had refractory disease and granulomatosis with polyangiitis (Wegener's). A glomerular filtration rate (GFR) ≤40 mL/min was associated with intolerance. Serious adverse events were common (55% MMF and 45% MS patients). Conclusions No differences in treatment tolerance were observed between the MS and MMF groups. Despite similar treatment intolerance, MS was associated with improved efficacy in PSV and SLE compared with MMF. However, baseline group imbalances in factors potentially affecting remission and relapse may have influenced the results. Treatment intolerance was common and strongly associated with low GFR. Further treatment trials are warranted to investigate the effect of GFR on mycophenolic acid pharmacokinetics and clinical outcomes (ISRCTN83027184; EUDRACT 2005-002207-16; Funding Novartis UK).09/2014; 7(6):562. DOI:10.1093/ckj/sfu096
- [Show abstract] [Hide abstract]
ABSTRACT: In this prospective study we investigated the impact of the proton pump inhibitor (PPI) pantoprazole on the bioavailability of mycophenolic acid (MPA) after oral administration of enteric-coated mycophenolate sodium (EC-MPS; Myfortic) in heart or lung transplant recipients. Previously we demonstrated that pantoprazole reduces the MPA exposure of mycophenolate mofetil (MMF; CellCept) by 34% in area under the concentration-time curve (AUC). Because gastrointestinal side-effects are common after organ transplantation, we investigated the effect of PPI on MPA levels in patients receiving EC-MPS. MPA plasma concentrations and inosine monophosphate dehydrogenase (IMPDH) activity at baseline, 30 minutes and 1, 2, 3 and 4 hours were obtained from 21 patients. These patients were treated with pantoprazole 40 mg once daily and EC-MPS twice daily at a mean dose of 960 mg. Measurements were repeated after pantoprazole withdrawal. MPA concentrations and IMPDH activities did not reveal any significant difference during PPI treatment and after withdrawal. MPA AUC, MPA C(max) (maximal MPA concentration), the time until C(max) was reached (T(max)) and IMPDH activity AUC all showed no significant difference. We did not find an influence of pantoprazole on EC-MPS pharmacokinetics such as we did for MMF in our previous investigation. A further prospective, large, cross-over study is planned to support these preliminary results. Given that MPA exposure by AUC correlates with the incidence of acute rejection episodes and transplant vasculopathy, the present findings may have clinical implications.The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 05/2011; 30(5):565-71. DOI:10.1016/j.healun.2010.12.003 · 5.61 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: There are few pharmacokinetic data for enteric-coated mycophenolate sodium (EC-MPS) in Chinese kidney transplant recipients. Previously, we demonstrated that patients with 540 mg EC-MPS reached target exposure on day 4 after transplantation. The aim of this study was further to confirm that mycophenolic acid (MPA) delivery with a daily total dose 1080 mg EC-MPS is adequate during the early-phase posttransplantation and preliminarily assess the pharmacokinetics after a single dose and multiple doses of EC-MPS in Chinese live-donor kidney transplant recipients. Twelve patients (eight men and four women, mean age 41.3 ± 6.78 years) treated with EC-MPS, cyclosporine and corticosteroids were included in this study. Patients received a single oral dose of EC-MPS 540 mg, then 540 mg twice daily. MPA concentrations were measured by high-performance liquid chromatography. Twelve-hour pharmacokinetic profiles were obtained after the single oral dose and multiple doses on day 4 postoperation. The pharmacokinetic parameters were compared between a single dose and multiple doses. By using multiple stepwise regression analysis, we obtained two predictive equations of MPA systemic exposure. Bland-Altman analysis was developed to test agreement between the observed MPA area under the concentration-time curve (AUC) and the predicted MPA AUC. The mean (range) MPA AUC was 42 ± 14.67 (29.29-75.95) mg/l h after the first dose, and 44.72 ± 14.57 (32.06-80.79) mg/l h on day 4 after operation. MPA exposure provided by a single dose and multiple doses were similar (p > 0.05). The best equations obtained were the following: 20.003 + 1.181C6 h + 7.22C8 h (r = 0.936) and 17.023 + 3.11C1 h + 1.245 + 4.988C8 h (r = 0.964). These equation models showed an optimal agreement between the observed MPA AUC and the predicted MPA AUC. Lower dosing of EC-MPS, compared with the standard dose (720 mg twice daily), may provide enough MPA exposure for Chinese live-donor kidney transplant patients on day 4. Given that the MPA exposure by AUC correlates with the incidence of acute rejection episodes and transplant vasculopathy, the present findings may have clinical implications, and the optimum dose range of EC-MPS for patients in all ranges of body weight should also be determined.International journal of clinical practice. Supplement 04/2014; 68(181):31-7. DOI:10.1111/ijcp.12404