EC-MPS in Chinese Organ Transplant Recipients
Perspective Enteric-coated mycophenolate sodium: an update W. Zhang,1,2,*, C. Ding1,2,*, S. Zheng1,2 1
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China 2 Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Mycophenolate mofetil (MMF), the first mycophenolic acid (MPA) formulation, has been used as a major immunosuppressive regimen in organ transplantation for over a decade. Treatment with MMF in combination with calcineurin inhibitors (CNIs) and steroids results in a spectacular decrease of acute rejection and prolongs allograft survival. MMF inhibits the proliferation of T and B lymphocytes by targeting the de novo pathway for purine biosynthesis (1,2). MPA also suppresses dendritic cell maturation, decreasing its capacity for antigen presentation to T lymphocytes. However, MMF is often associated with gastrointestinal (GI) complications that can lead to dose reduction or discontinuation. Such dosage reductions increase the incidence of acute rejection and lead to subsequent graft loss (3–6). Enteric-coated mycophenolate sodium (EC-MPS) is an enteric-coated formulation based on the sodium salt of MPA. It has been demonstrated to provide equivalent MPA exposure and to have similar effects on inosine monophosphate dehydrogenase (IMPDH) enzyme activity. This Perspective aims to summarise the recent data on the clinical implications of EC-MPS treatment in organ transplantation and other diseases.
Pharmacokinetic and pharmacodynamic study of EC-MPS Enteric-coated mycophenolate sodium is an alternative MPA formulation. However, the kinetics of EC-MPS differ in that the drug is
enteric coated, dissolves at pH levels of ≥ 5, with the goal of delaying the delivery of MPA until it reaches the small intestine (7), thus delaying the time to maximum concentration compared with that of MMF. According to the pharmacokinetic studies, 720 mg EC-MPS provides a bioequivalent MPA exposure to that of 1000 mg MMF, and has a comparable safety profile (8,9). The pharmacodynamic response of IMPDH enzyme inhibition has been demonstrated to be similar (10). Furthermore, MPA metabolite exposure and maximum plasma MPA concentrations have confirmed the bioequivalence of EC-MPS and MMF through a meta-analysis of three clinical trials (11).
Implication of EC-MPS in autoimmune diseases The role of EC-MPS is still controversial in the treatment of autoimmune diseases (12), such as proliferative lupus nephritis (PLN) and progressive IgA nephritis. Traitanon et al. (13) reported its efficacy and safety in the treatment of resistant-type PLN. Thirty-one renal biopsy-proven PLN patients, who had failed to respond to intravenous cyclophosphamide (IVCY), were divided into two groups: EC-MPS (n = 15) vs. extended-course IVCY (n = 16). After 6 months of treatment, fewer adverse events and a significant improvement in histology were observed in the EC-MPS group. EC-MPS has been shown to be more efficacious and to be a better tolerated therapeutic option for resistant-type PLN. For patients with progressive IgA
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68 (Suppl. 181), 1–3 doi: 10.1111/ijcp.12399
Correspondence to: Prof. Shusen Zheng, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 79 Qingchun Road, Zhejiang 310003, China Tel.: + 86-571-87236601 Fax: + 86-571-87236739 Email: [email protected]. *These authors contributed equally to this work. Disclosure Publication of this supplement article was supported as part of an unrestricted educational grant by Novartis. Novartis provided financial support for English-language editorial services. The authors declare that they do not have any potential conflict of interest with respect to this manuscript.
nephritis, Czock et al. (14) enrolled seven cases for a randomised, open-label, crossover study. Pharmacokinetics and pharmacodynamic analyses were performed. EC-MPS has been shown to obtain a higher overall exposure of MPA and a lower apparent clearance compared with MMF. While IMPDH differences were not observed between EC-MPS and MMF, EC-MPS might be an effective alternative for immunosuppressive treatment of patients with progressive IgA nephritis.
Safety and efficacy of EC-MPS vs. MMF in organ transplantation The majority of data concerning the safety and tolerability of EC-MPS vs. MMF in transplant recipients were obtained from two different kinds of study. One kind of study compared the incidence of acute rejection and graft loss between groups initiated on EC-MPS and MMF treatment (Table 1). EC-MPS has been demonstrated to be associated with fewer dose manipulations and
1
2
Perspective
Table 1 Initial study on EC-MPS and MMF
Patients (n)
BPAR incidence (%)
Graft loss (%)
Study
Year
Study design
Follow-up period
EC-MPS
MMF
EC-MPS
MMF
p value
EC-MPS
MMF
p value
Salvadori et al. (20)
2004
12 months
213
210
22.50
24.30
NS
5.20
6.70
NS
Ciancio et al. (21)
2008
1 year
75
75
3.00
9.00
0.09
2.67
2.67
NS
Cooper et al. (22)
2009
3 months
193
186
14.00
23.10
0.0221
NA
NA
NA
Sollinger et al. (23)
2010
2 years
598
1111
21.90
30.20
0.0004
NA
NA
NA
Irish et al. (24)
2010
A phase III, international, randomised, double-blind, parallel study A single-centre, prospective, open-label randomised trial Two teaching hospitals, retrospective cohort study A single centre, retrospective study OPTN/UNOS database
3 years
5057
43,401
13.60
11.70
0.002
9.90
12.10
0.945
.......................................................................
.......................................................................
BPAR, biopsy-proven acute rejection; EC-MPS, enteric-coated mycophenolate sodium; MMF, mycophenolate mofetil; NS, not significant; NA, not applicable.
Table 2 Converted study on EC-MPS and MMF
Study
Year
Study design
Chan et al. (25)
2006
A multicentre, open-label, prospective study
Bolin et al. (26)
2007
Shehata et al. (27)
Follow-up period
Group
EC-MPS vs. control
EC-MPS
Control
Outcome I
Outcome II
4–6 weeks
Patients experiencing GI complaints converted to equimolar EC-MPS (n = 117)
Patients without GI complaints remained on MMF (n = 101)
GSRS, GIQLI and PGWBI subscale scores improved significantly
A prospective, multicentre, longitudinal, open-label trial
3 months
Patients with GI symptoms converted to equimolar doses of EC-MPS (n = 728)
NA
2009
A randomised, multicentre, open-label trial
12 weeks
Patients experiencing GI complaints converted to equimolar EC-MPS (n = 68)
Langone et al. (28)
2011
A multicentre, randomised, prospective, double-blind, parallel-group trial
4 weeks
Ortega et al. (29)
2011
A randomised, multicentre, open-labelled study
12 weeks
Patients with GI symptoms randomised to an equimolar dose of EC-MPS + MMF placebo (n = 199) Patients with GI adverse events randomised to EC-MPS (n = 59)
Patients experiencing GI complaints remained on MMF (n = 61) Patients with GI symptoms randomised to continue on MMF-based regimen + EC-MPS placebo (n = 197) Patients with GI adverse events randomised to continue with MMF (n = 54)
A significant improvement in GSRS score from baseline to month 1, sustained to month 3 Greater proportion of patients receiving a higher MPA dose at week 12 than at randomisation Significantly greater decrease in the GSRS indigestion syndrome dimension
Mean improvements in all GSRS and most GIQLI subscores exceeded which remained stable in MMF group A significant improvement in GSRS subscale scores in the total population More EC-MPS patients receiving the maximum recommended dose
.......................................................................
Baseline-adjusted mean global scores in GI quality of life index were significantly higher
Particularly in patients with indigestion, diabetes, on steroids would benefit from the conversion
All secondary scales indicated better HRQoL, higher percentage of patients receiving intermediate doses of MPA
....................................................................... EC-MPS, enteric-coated mycophenolate sodium; MMF, mycophenolate mofetil; GSRS, gastrointestinal symptom rating scale; GIQLI, gastrointestinal quality of life index; PGWBI, psychological general well-being index; HRQoL, health-related quality of life.
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68 (Suppl. 181), 1–3
Perspective
a lower incidence of biopsy-proven acute rejection (BPAR). The other kind of study focused on patients experiencing GI complaints, following conversion to EC-MPS (Table 2). EC-MPS is an alternative formulation of MPA, designed to reduce GI toxicity. These studies have shown that on switching to EC-MPS, GI-related symptoms and healthrelated quality of life improved significantly and were sustained over time.
Intensified dosing of EC-MPS and steroids or CNI minimisation Adequate MPA exposure within the first few weeks post-transplantation is crucial for allograft outcomes. Because of delaying the release of MPA to the systemic circulation, an early EC-MPS intensified dosing (ID) regimen has been investigated. The feasibility and safety of EC-MPS ID were studied according to phase I of the pharmacokinetic pilot study (15). The ID regimen significantly reduced the rates of BPAR, compared with the standard dosing regimen (16). Moreover, similar results have been confirmed through a meta-analysis (17). The combination of MPA with steroids and CNI has become a standard immunosuppressive protocol. But the side-effects, including CNI nephrotoxicity, steroid-related metabolic syndrome and osteoporosis, have been taken into account. The EC-MPS ID regimen enabled either a lower CSA exposure (18) or steroid avoidance (19) without compromising the therapeutic efficacy.
Conclusion and perspectives Enteric-coated mycophenolate sodium served as an immunosuppressive drug, in combination with CNIs and steroids, to prevent acute rejection post solid organ transplantation, which can delay the delivery of MPA until reaching the small intestine, thus improving GI toxicities compared with MMF. There are still no data indicating a difference in haematology side effects between EC-MPS and MMF. ID with EC-MPS can permit steroid avoidance or the minimisation of CNIs, which confirmed the efficacy and safety of this formulation. The majority of the clinical trials were done in kidney transplant patients, whereas a small proportion were in liver transplant patients. With the extensive application of EC-MPS because of its clinical superiority, it will be widely accepted by liver transplant patients and physicians, and actually benefit liver transplantation. It is hoped to use EC-MPS in clinical transplant practice and has wider application prospects.
Acknowledgements This work was supported by grants from the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (Grant no. 81121002), National S&T Major Project (no. 2012ZX10002017) and the National Natural Science Foundation of China (no. 81000065).
References 1 Allison AC, Hovi T, Watts RW, Webster AD. Immunological observations on patients with Lesch-Nyhan syndrome, and on the role of de-novo purine synthesis in lymphocyte transformation. Lancet 1975; 2(7946): 1179–83. 2 Allison AC, Eugui EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev 1993; 136: 5–28. 3 Knoll GA, MacDonald I, Khan A, Van Walraven C. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol 2003; 14(9): 2381–6. 4 Tierce JC, Porterfield-Baxa J, Petrilla AA, Kilburg A, Ferguson RM. Impact of mycophenolate mofetil (MMF)-related gastrointestinal complications and MMF dose alterations on transplant outcomes and healthcare costs in renal transplant recipients. Clin Transplant 2005; 19(6): 779–84. 5 Hardinger KL, Brennan DC, Lowell J, Schnitzler MA. Long-term outcome of gastrointestinal complications in renal transplant patients treated with mycophenolate mofetil. Transpl Int 2004; 17(10): 609–16. 6 Bunnapradist S, Lentine KL, Burroughs TE et al. Mycophenolate mofetil dose reductions and discontinuations after gastrointestinal complications are associated with renal transplant graft failure. Transplantation 2006; 82(1): 102–7. 7 Arns W, Breuer S, Choudhury S et al. Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil. Clin Transplant 2005; 19(2): 199–206. 8 Tedesco-Silva H, Bastien MC, Choi L et al. Mycophenolic acid metabolite profile in renal transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil. Transplant Proc 2005; 37(2): 852–5. 9 Arns W, Gies M, Choi L et al. Absorption characteristics of EC-MPS – an enteric-coated formulation of mycophenolic sodium. Int J Clin Pharmacol Ther 2006; 44(8): 375–85. 10 Budde K, Bauer S, Hambach P et al. Pharmacokinetic and pharmacodynamic comparison of enteric-coated mycophenolate sodium and mycophenolate mofetil in maintenance renal transplant patients. Am J Transplant 2007; 7 (4): 888–98. 11 Johnston A, He X, Holt DW. Bioequivalence of entericcoated mycophenolate sodium and mycophenolate mofetil: a meta-analysis of three studies in stable renal transplant recipients. Transplantation 2006; 82(11): 1413–8. 12 Abd Rahman AN, Tett SE, Staatz CE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease. Clin Pharmacokinet 2013; 52(5): 303–31. 13 Traitanon O, Avihingsanon Y, Kittikovit V et al. Efficacy of enteric-coated mycophenolate sodium in patients with resistant-type lupus nephritis: a prospective study. Lupus 2008; 17(8): 744–51. 14 Czock D, Rasche FM, Carius A et al. Pharmacokinetics and pharmacodynamics of mycophenolic acid after enteric-coated mycophenolate versus mycophenolate mofetil in patients with progressive IgA nephritis. J Clin Pharmacol 2007; 47(7): 850–9. 15 Glander P, Sommerer C, Arns W et al. Pharmacokinetics and pharmacodynamics of intensified versus standard dosing of mycophenolate sodium in renal transplant patients. Clin J Am Soc Nephrol 2010; 5(3): 503–11.
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68 (Suppl. 181), 1–3
3
16 Sommerer C, Glander P, Arns W et al. Safety and efficacy of intensified versus standard dosing regimens of entericcoated mycophenolate sodium in de novo renal transplant patients. Transplantation 2011; 91(7): 779–85. 17 Budde K, Tedesco-Silva H, Arns W et al. Improved rejection prophylaxis with an initially intensified dosing regimen of enteric-coated mycophenolate sodium in de novo renal transplant recipients. Transplantation 2011; 92(3): 321–7. 18 Chadban S, Eris J, Russ G et al. Enteric-coated mycophenolate sodium in combination with full dose or reduced dose cyclosporine, basiliximab and corticosteroids in Australian de novo kidney transplant patients. Nephrology (Carlton) 2013; 18(1): 63–70. 19 Thierry A, Mourad G, Buchler M et al. Steroid avoidance with early intensified dosing of enteric-coated mycophenolate sodium: a randomized multicentre trial in kidney transplant recipients. Nephrol Dial Transplant 2012; 27(9): 3651–9. 20 Salvadori M, Holzer H, de Mattos A et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2004; 4(2): 231–6. 21 Ciancio G, Burke GW, Gaynor JJ et al. Randomized trial of mycophenolate mofetil versus enteric-coated mycophenolate sodium in primary renal transplant recipients given tacrolimus and daclizumab/thymoglobulin: one year follow-up. Transplantation 2008; 86(1): 67–74. 22 Cooper M, Deering KL, Slakey DP et al. Comparing outcomes associated with dose manipulations of enteric-coated mycophenolate sodium versus mycophenolate mofetil in renal transplant recipients. Transplantation 2009; 88(4): 514–20. 23 Sollinger HW, Sundberg AK, Leverson G, Voss BJ, Pirsch JD. Mycophenolate mofetil versus enteric-coated mycophenolate sodium: a large, single-center comparison of dose adjustments and outcomes in kidney transplant recipients. Transplantation 2010; 89(4): 446–51. 24 Irish W, Arcona S, Gifford RJ, Baillie GM, Cooper M. Enteric-coated mycophenolate sodium versus mycophenolate mofetil maintenance immunosuppression: outcomes analysis of the United Network for Organ Sharing/Organ Procurement and Transplantation Network database. Transplantation 2010; 90(1): 23–30. 25 Chan L, Mulgaonkar S, Walker R, Arns W, Ambuhl P, Schiavelli R. Patient-reported gastrointestinal symptom burden and health-related quality of life following conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium. Transplantation 2006; 81(9): 1290–7. 26 Bolin P, Tanriover B, Zibari GB et al. Improvement in 3-month patient-reported gastrointestinal symptoms after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in renal transplant patients. Transplantation 2007; 84(11): 1443–51. 27 Shehata M, Bhandari S, Venkat-Raman G et al. Effect of conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium on maximum tolerated dose and gastrointestinal symptoms following kidney transplantation. Transpl Int 2009; 22(8): 821–30. 28 Langone AJ, Chan L, Bolin P, Cooper M. Enteric-coated mycophenolate sodium versus mycophenolate mofetil in renal transplant recipients experiencing gastrointestinal intolerance: a multicenter, double-blind, randomized study. Transplantation 2011; 91(4): 470–8. 29 Ortega F, Sanchez-Fructuoso A, Cruzado JM et al. Gastrointestinal quality of life improvement of renal transplant recipients converted from mycophenolate mofetil to enteric-coated mycophenolate sodium drugs or agents: mycophenolate mofetil and enteric-coated mycophenolate sodium. Transplantation 2011; 92(4): 426–32.
Paper received July 2013, accepted December 2013
Perspective Enteric-coated mycophenolate sodium: an update W. Zhang,1,2,*, C. Ding1,2,*, S. Zheng1,2 1
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China 2 Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Mycophenolate mofetil (MMF), the first mycophenolic acid (MPA) formulation, has been used as a major immunosuppressive regimen in organ transplantation for over a decade. Treatment with MMF in combination with calcineurin inhibitors (CNIs) and steroids results in a spectacular decrease of acute rejection and prolongs allograft survival. MMF inhibits the proliferation of T and B lymphocytes by targeting the de novo pathway for purine biosynthesis (1,2). MPA also suppresses dendritic cell maturation, decreasing its capacity for antigen presentation to T lymphocytes. However, MMF is often associated with gastrointestinal (GI) complications that can lead to dose reduction or discontinuation. Such dosage reductions increase the incidence of acute rejection and lead to subsequent graft loss (3–6). Enteric-coated mycophenolate sodium (EC-MPS) is an enteric-coated formulation based on the sodium salt of MPA. It has been demonstrated to provide equivalent MPA exposure and to have similar effects on inosine monophosphate dehydrogenase (IMPDH) enzyme activity. This Perspective aims to summarise the recent data on the clinical implications of EC-MPS treatment in organ transplantation and other diseases.
Pharmacokinetic and pharmacodynamic study of EC-MPS Enteric-coated mycophenolate sodium is an alternative MPA formulation. However, the kinetics of EC-MPS differ in that the drug is
enteric coated, dissolves at pH levels of ≥ 5, with the goal of delaying the delivery of MPA until it reaches the small intestine (7), thus delaying the time to maximum concentration compared with that of MMF. According to the pharmacokinetic studies, 720 mg EC-MPS provides a bioequivalent MPA exposure to that of 1000 mg MMF, and has a comparable safety profile (8,9). The pharmacodynamic response of IMPDH enzyme inhibition has been demonstrated to be similar (10). Furthermore, MPA metabolite exposure and maximum plasma MPA concentrations have confirmed the bioequivalence of EC-MPS and MMF through a meta-analysis of three clinical trials (11).
Implication of EC-MPS in autoimmune diseases The role of EC-MPS is still controversial in the treatment of autoimmune diseases (12), such as proliferative lupus nephritis (PLN) and progressive IgA nephritis. Traitanon et al. (13) reported its efficacy and safety in the treatment of resistant-type PLN. Thirty-one renal biopsy-proven PLN patients, who had failed to respond to intravenous cyclophosphamide (IVCY), were divided into two groups: EC-MPS (n = 15) vs. extended-course IVCY (n = 16). After 6 months of treatment, fewer adverse events and a significant improvement in histology were observed in the EC-MPS group. EC-MPS has been shown to be more efficacious and to be a better tolerated therapeutic option for resistant-type PLN. For patients with progressive IgA
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68 (Suppl. 181), 1–3 doi: 10.1111/ijcp.12399
Correspondence to: Prof. Shusen Zheng, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 79 Qingchun Road, Zhejiang 310003, China Tel.: + 86-571-87236601 Fax: + 86-571-87236739 Email: [email protected]. *These authors contributed equally to this work. Disclosure Publication of this supplement article was supported as part of an unrestricted educational grant by Novartis. Novartis provided financial support for English-language editorial services. The authors declare that they do not have any potential conflict of interest with respect to this manuscript.
nephritis, Czock et al. (14) enrolled seven cases for a randomised, open-label, crossover study. Pharmacokinetics and pharmacodynamic analyses were performed. EC-MPS has been shown to obtain a higher overall exposure of MPA and a lower apparent clearance compared with MMF. While IMPDH differences were not observed between EC-MPS and MMF, EC-MPS might be an effective alternative for immunosuppressive treatment of patients with progressive IgA nephritis.
Safety and efficacy of EC-MPS vs. MMF in organ transplantation The majority of data concerning the safety and tolerability of EC-MPS vs. MMF in transplant recipients were obtained from two different kinds of study. One kind of study compared the incidence of acute rejection and graft loss between groups initiated on EC-MPS and MMF treatment (Table 1). EC-MPS has been demonstrated to be associated with fewer dose manipulations and
1
2
Perspective
Table 1 Initial study on EC-MPS and MMF
Patients (n)
BPAR incidence (%)
Graft loss (%)
Study
Year
Study design
Follow-up period
EC-MPS
MMF
EC-MPS
MMF
p value
EC-MPS
MMF
p value
Salvadori et al. (20)
2004
12 months
213
210
22.50
24.30
NS
5.20
6.70
NS
Ciancio et al. (21)
2008
1 year
75
75
3.00
9.00
0.09
2.67
2.67
NS
Cooper et al. (22)
2009
3 months
193
186
14.00
23.10
0.0221
NA
NA
NA
Sollinger et al. (23)
2010
2 years
598
1111
21.90
30.20
0.0004
NA
NA
NA
Irish et al. (24)
2010
A phase III, international, randomised, double-blind, parallel study A single-centre, prospective, open-label randomised trial Two teaching hospitals, retrospective cohort study A single centre, retrospective study OPTN/UNOS database
3 years
5057
43,401
13.60
11.70
0.002
9.90
12.10
0.945
.......................................................................
.......................................................................
BPAR, biopsy-proven acute rejection; EC-MPS, enteric-coated mycophenolate sodium; MMF, mycophenolate mofetil; NS, not significant; NA, not applicable.
Table 2 Converted study on EC-MPS and MMF
Study
Year
Study design
Chan et al. (25)
2006
A multicentre, open-label, prospective study
Bolin et al. (26)
2007
Shehata et al. (27)
Follow-up period
Group
EC-MPS vs. control
EC-MPS
Control
Outcome I
Outcome II
4–6 weeks
Patients experiencing GI complaints converted to equimolar EC-MPS (n = 117)
Patients without GI complaints remained on MMF (n = 101)
GSRS, GIQLI and PGWBI subscale scores improved significantly
A prospective, multicentre, longitudinal, open-label trial
3 months
Patients with GI symptoms converted to equimolar doses of EC-MPS (n = 728)
NA
2009
A randomised, multicentre, open-label trial
12 weeks
Patients experiencing GI complaints converted to equimolar EC-MPS (n = 68)
Langone et al. (28)
2011
A multicentre, randomised, prospective, double-blind, parallel-group trial
4 weeks
Ortega et al. (29)
2011
A randomised, multicentre, open-labelled study
12 weeks
Patients with GI symptoms randomised to an equimolar dose of EC-MPS + MMF placebo (n = 199) Patients with GI adverse events randomised to EC-MPS (n = 59)
Patients experiencing GI complaints remained on MMF (n = 61) Patients with GI symptoms randomised to continue on MMF-based regimen + EC-MPS placebo (n = 197) Patients with GI adverse events randomised to continue with MMF (n = 54)
A significant improvement in GSRS score from baseline to month 1, sustained to month 3 Greater proportion of patients receiving a higher MPA dose at week 12 than at randomisation Significantly greater decrease in the GSRS indigestion syndrome dimension
Mean improvements in all GSRS and most GIQLI subscores exceeded which remained stable in MMF group A significant improvement in GSRS subscale scores in the total population More EC-MPS patients receiving the maximum recommended dose
.......................................................................
Baseline-adjusted mean global scores in GI quality of life index were significantly higher
Particularly in patients with indigestion, diabetes, on steroids would benefit from the conversion
All secondary scales indicated better HRQoL, higher percentage of patients receiving intermediate doses of MPA
....................................................................... EC-MPS, enteric-coated mycophenolate sodium; MMF, mycophenolate mofetil; GSRS, gastrointestinal symptom rating scale; GIQLI, gastrointestinal quality of life index; PGWBI, psychological general well-being index; HRQoL, health-related quality of life.
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68 (Suppl. 181), 1–3
Perspective
a lower incidence of biopsy-proven acute rejection (BPAR). The other kind of study focused on patients experiencing GI complaints, following conversion to EC-MPS (Table 2). EC-MPS is an alternative formulation of MPA, designed to reduce GI toxicity. These studies have shown that on switching to EC-MPS, GI-related symptoms and healthrelated quality of life improved significantly and were sustained over time.
Intensified dosing of EC-MPS and steroids or CNI minimisation Adequate MPA exposure within the first few weeks post-transplantation is crucial for allograft outcomes. Because of delaying the release of MPA to the systemic circulation, an early EC-MPS intensified dosing (ID) regimen has been investigated. The feasibility and safety of EC-MPS ID were studied according to phase I of the pharmacokinetic pilot study (15). The ID regimen significantly reduced the rates of BPAR, compared with the standard dosing regimen (16). Moreover, similar results have been confirmed through a meta-analysis (17). The combination of MPA with steroids and CNI has become a standard immunosuppressive protocol. But the side-effects, including CNI nephrotoxicity, steroid-related metabolic syndrome and osteoporosis, have been taken into account. The EC-MPS ID regimen enabled either a lower CSA exposure (18) or steroid avoidance (19) without compromising the therapeutic efficacy.
Conclusion and perspectives Enteric-coated mycophenolate sodium served as an immunosuppressive drug, in combination with CNIs and steroids, to prevent acute rejection post solid organ transplantation, which can delay the delivery of MPA until reaching the small intestine, thus improving GI toxicities compared with MMF. There are still no data indicating a difference in haematology side effects between EC-MPS and MMF. ID with EC-MPS can permit steroid avoidance or the minimisation of CNIs, which confirmed the efficacy and safety of this formulation. The majority of the clinical trials were done in kidney transplant patients, whereas a small proportion were in liver transplant patients. With the extensive application of EC-MPS because of its clinical superiority, it will be widely accepted by liver transplant patients and physicians, and actually benefit liver transplantation. It is hoped to use EC-MPS in clinical transplant practice and has wider application prospects.
Acknowledgements This work was supported by grants from the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (Grant no. 81121002), National S&T Major Project (no. 2012ZX10002017) and the National Natural Science Foundation of China (no. 81000065).
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Paper received July 2013, accepted December 2013
