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Efficacy and safety of mycophenolate mofetil in different dosages in Asian renal allograft recipients
Efficacy and Safety of Mycophenolate Mofetil in Different Dosages in Asian Renal Allograft Recipients W.K. Tsang, K.L. Tong, S. Yeung, W. Lee, and H.W.H. Chan
M
YCOPHENOLATE mofetil (MMF) is a potent new immunosuppressive agent that selectively inhibits the proliferation of T and B lymphocytes, the production of antibodies, and the generation of cytotoxic T cells in response to immune stimuli. MMF has been shown to be superior to azathioprine (AZA) in combination with cyclosporine A (CsA) and steroid in preventing acute cellular rejection in the first 6 months following renal transplantation.1,2 This reduction can be achieved with MMF daily doses of 2 g or 3 g. However, the side effects, including diarrhea, abdominal cramps, leucopenia, and cytomegalovirus (CMV) disease, are more frequently found in the patients treated with 3 g.3,4 The percentage of patients withdrawing due to an adverse event was also higher in the MMF 3 g group, thus leading to the recommendation of 2 g/d as the optimal dose in triple therapy. However, it varies in special patient groups. The USA MMF Trial identified African-Americans as high-risk patients who derived significant benefit from higher doses.5 The optimal dosage of MMF in the Chinese or Asian population has yet to be determined. Wang et al has shown that in Chinese allograft recipients, the efficacy and safety of MMF in 2 g/d and 1.5 g/d with CsA and steroid in preventing rejection are comparable.6 The objective of this study was to compare the efficacy and safety of MMF in different dosages in Chinese renal allograft recipients. MATERIALS AND METHODS From 1997 to 1998, 69 renal allograft recipients (43 males and 26 females) were enrolled into two groups: MMF and AZA. All were treated simultaneously with CsA (Neoral) and prednisolone. The initial and maintenance doses of CsA were 10 mg/kg per day and 3 to 5 mg/kg per day, respectively. The dosages were adjusted according to whole blood CsA trough level using monoclonal Tdx assay. The initial and maintenance doses of prednisolone were 30 mg/day and 0.1 to 0.2 mg/kg per day. Forty-one patients were treated with three different dosages of MMF twice daily: MMF 2 g/d (18/41), MMF 1.5 g/d (14/41), and MMF 1 g/d (9/41). The AZA group included 28 patients receiving 1 to 2 mg/kg per day AZA. During every follow-up visit, parameters, including adverse effects, opportunistic infection, CsA trough level, serum creatinine, and complete blood count, were checked. In the protocol, first-line treatment for biopsy-proven acute rejection was 500 mg intravenous methylprednisolone for 3 consecutive days. Steroid-resistant rejection was to be treated with OKT3 or converted to tacrolimus.
The data were analysed using Wilcoxon rank sum test. Adverse events were analysed with Fisher Exact Test.
RESULTS
There was no significant difference in sex, age, body weight, or primary renal disease in MMF and AZA groups. The mean dosages of MMF and AZA were 1.6 ⫾ 0.4 g/d and 75.9 ⫾ 21 mg/day, respectively. MMF significantly reduced the incidence of acute rejection when compared with AZA (14.6% vs 32.1%; P ⬍ .05). Among three subgroups receiving three different dosages of MMF, there was no significant difference in the incidence of acute rejection: 3/18 (16.7%) in MMF 2 g/d group, 2/14 (14.3%) in MMF 1.5 g/d group, and 1/9 (11.1%) in MMF 1 g/d group. Patient survival at 6 months was 100% in MMF group versus 93% in AZA group. Graft survival at 6 months was 97% in MMF group versus 93% in AZA group (P ⫽ NS). There was no statistical difference in serum creatinine level at 6 months between MMF and AZA groups (139.2 ⫾ 37.9 mol/L vs 138.0 ⫾ 31.5 mol/L). Adverse effects, including leucopenia and gastrointestinal discomfort, were similar in both groups. The incidence of CMV infection was 14.6% in MMF group compared with 10.7% in AZA group (P ⫽ NS). However, among three subgroups receiving different dosages of MMF, the incidence of CMV infection was 27.8% in MMF 2 g/d when compared with 7.1% in MMF 1.5 g/d, and 0% in MMF 1 g/d (P ⫽ .04). CONCLUSION
In our study, MMF was very effective in reducing the incidence of acute cellular rejection by 55% in the first 6 months when compared with AZA in triple therapy in combination with CsA and steroid. Three large-scale clinical trials conducted in North America, Europe, and Australia show that MMF decreases the incidence of acute allograft rejection in the first 6 months after transplant when compared with placebo or AZA.1–3 The severity of From the Division of Nephrology, Department of Medicine and Geriatrics, Princess Margaret Hospital, Kwai Chung, Hong Kong, China. Address reprint requests to Dr W.K. Tsang, Division of Nephrology, Department of Medicine and Geriatrics, Princess Margaret Hospital, Kwai Chung, Hong Kong, China.
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/00/$–see front matter PII S0041-1345(00)01389-0
Transplantation Proceedings, 32, 1755–1756 (2000)
1755
1756
the biopsy-proven rejection episodes is also reduced.3 Similar to other studies, we show that there is no significant difference in 6-month graft and patient survival rates and CMV infection in patients on MMF when compared with AZA. To find the optimal dose of MMF in Chinese renal allograft recipients in preventing rejection effectively with acceptable adverse effects, patients were stratified to three different dosages of MMF. There is no significant difference in acute rejection episodes at 6 months among the three MMF subgroups. We suggest that a lower dosage of MMF can be used in the Chinese population. This has been supported by another study that shows that MMF 1.5 g/d has comparable efficacy as MMF 2 g/day, with similar mycophenolic acid area under-the-curve (MPA-AUC) values.6 It has been shown that the MMF dosage is significantly related to the occurrence of adverse effects, including CMV infection. In our study, patients on MMF 2 g/d had
TSANG, TONG, YEUNG ET AL
significantly more frequent CMV infection than the other two subgroups with smaller dosages. It is reasonable to use a dose of 1.5 g/d MMF in low-risk Chinese patients. Prospective studies using different dosages of MMF with MPA-AUC measurement and longer duration of follow-up should be conducted to find the optimal dose of MMF in Chinese patients. REFERENCES 1. The Mycophenolate Mofetil Renal Refractory Rejection Study Group: Transplantation 61:722, 1996 2. The Tricontinental Mycophenolate Mofetil Renal Transplant Group: Transplantation 61:1029, 1996 3. European Mycophenolate Mofetil Cooperative Study Group: Lancet 345:1321, 1995 4. Mathew TH, et al: Transplantation 65:1450, 1998 5. Neylan JF, et al: Transplantation 64:1277, 1997 6. Wang X, Tang X, Xu D: Transplantation Proc 30:3573, 1998
M
YCOPHENOLATE mofetil (MMF) is a potent new immunosuppressive agent that selectively inhibits the proliferation of T and B lymphocytes, the production of antibodies, and the generation of cytotoxic T cells in response to immune stimuli. MMF has been shown to be superior to azathioprine (AZA) in combination with cyclosporine A (CsA) and steroid in preventing acute cellular rejection in the first 6 months following renal transplantation.1,2 This reduction can be achieved with MMF daily doses of 2 g or 3 g. However, the side effects, including diarrhea, abdominal cramps, leucopenia, and cytomegalovirus (CMV) disease, are more frequently found in the patients treated with 3 g.3,4 The percentage of patients withdrawing due to an adverse event was also higher in the MMF 3 g group, thus leading to the recommendation of 2 g/d as the optimal dose in triple therapy. However, it varies in special patient groups. The USA MMF Trial identified African-Americans as high-risk patients who derived significant benefit from higher doses.5 The optimal dosage of MMF in the Chinese or Asian population has yet to be determined. Wang et al has shown that in Chinese allograft recipients, the efficacy and safety of MMF in 2 g/d and 1.5 g/d with CsA and steroid in preventing rejection are comparable.6 The objective of this study was to compare the efficacy and safety of MMF in different dosages in Chinese renal allograft recipients. MATERIALS AND METHODS From 1997 to 1998, 69 renal allograft recipients (43 males and 26 females) were enrolled into two groups: MMF and AZA. All were treated simultaneously with CsA (Neoral) and prednisolone. The initial and maintenance doses of CsA were 10 mg/kg per day and 3 to 5 mg/kg per day, respectively. The dosages were adjusted according to whole blood CsA trough level using monoclonal Tdx assay. The initial and maintenance doses of prednisolone were 30 mg/day and 0.1 to 0.2 mg/kg per day. Forty-one patients were treated with three different dosages of MMF twice daily: MMF 2 g/d (18/41), MMF 1.5 g/d (14/41), and MMF 1 g/d (9/41). The AZA group included 28 patients receiving 1 to 2 mg/kg per day AZA. During every follow-up visit, parameters, including adverse effects, opportunistic infection, CsA trough level, serum creatinine, and complete blood count, were checked. In the protocol, first-line treatment for biopsy-proven acute rejection was 500 mg intravenous methylprednisolone for 3 consecutive days. Steroid-resistant rejection was to be treated with OKT3 or converted to tacrolimus.
The data were analysed using Wilcoxon rank sum test. Adverse events were analysed with Fisher Exact Test.
RESULTS
There was no significant difference in sex, age, body weight, or primary renal disease in MMF and AZA groups. The mean dosages of MMF and AZA were 1.6 ⫾ 0.4 g/d and 75.9 ⫾ 21 mg/day, respectively. MMF significantly reduced the incidence of acute rejection when compared with AZA (14.6% vs 32.1%; P ⬍ .05). Among three subgroups receiving three different dosages of MMF, there was no significant difference in the incidence of acute rejection: 3/18 (16.7%) in MMF 2 g/d group, 2/14 (14.3%) in MMF 1.5 g/d group, and 1/9 (11.1%) in MMF 1 g/d group. Patient survival at 6 months was 100% in MMF group versus 93% in AZA group. Graft survival at 6 months was 97% in MMF group versus 93% in AZA group (P ⫽ NS). There was no statistical difference in serum creatinine level at 6 months between MMF and AZA groups (139.2 ⫾ 37.9 mol/L vs 138.0 ⫾ 31.5 mol/L). Adverse effects, including leucopenia and gastrointestinal discomfort, were similar in both groups. The incidence of CMV infection was 14.6% in MMF group compared with 10.7% in AZA group (P ⫽ NS). However, among three subgroups receiving different dosages of MMF, the incidence of CMV infection was 27.8% in MMF 2 g/d when compared with 7.1% in MMF 1.5 g/d, and 0% in MMF 1 g/d (P ⫽ .04). CONCLUSION
In our study, MMF was very effective in reducing the incidence of acute cellular rejection by 55% in the first 6 months when compared with AZA in triple therapy in combination with CsA and steroid. Three large-scale clinical trials conducted in North America, Europe, and Australia show that MMF decreases the incidence of acute allograft rejection in the first 6 months after transplant when compared with placebo or AZA.1–3 The severity of From the Division of Nephrology, Department of Medicine and Geriatrics, Princess Margaret Hospital, Kwai Chung, Hong Kong, China. Address reprint requests to Dr W.K. Tsang, Division of Nephrology, Department of Medicine and Geriatrics, Princess Margaret Hospital, Kwai Chung, Hong Kong, China.
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/00/$–see front matter PII S0041-1345(00)01389-0
Transplantation Proceedings, 32, 1755–1756 (2000)
1755
1756
the biopsy-proven rejection episodes is also reduced.3 Similar to other studies, we show that there is no significant difference in 6-month graft and patient survival rates and CMV infection in patients on MMF when compared with AZA. To find the optimal dose of MMF in Chinese renal allograft recipients in preventing rejection effectively with acceptable adverse effects, patients were stratified to three different dosages of MMF. There is no significant difference in acute rejection episodes at 6 months among the three MMF subgroups. We suggest that a lower dosage of MMF can be used in the Chinese population. This has been supported by another study that shows that MMF 1.5 g/d has comparable efficacy as MMF 2 g/day, with similar mycophenolic acid area under-the-curve (MPA-AUC) values.6 It has been shown that the MMF dosage is significantly related to the occurrence of adverse effects, including CMV infection. In our study, patients on MMF 2 g/d had
TSANG, TONG, YEUNG ET AL
significantly more frequent CMV infection than the other two subgroups with smaller dosages. It is reasonable to use a dose of 1.5 g/d MMF in low-risk Chinese patients. Prospective studies using different dosages of MMF with MPA-AUC measurement and longer duration of follow-up should be conducted to find the optimal dose of MMF in Chinese patients. REFERENCES 1. The Mycophenolate Mofetil Renal Refractory Rejection Study Group: Transplantation 61:722, 1996 2. The Tricontinental Mycophenolate Mofetil Renal Transplant Group: Transplantation 61:1029, 1996 3. European Mycophenolate Mofetil Cooperative Study Group: Lancet 345:1321, 1995 4. Mathew TH, et al: Transplantation 65:1450, 1998 5. Neylan JF, et al: Transplantation 64:1277, 1997 6. Wang X, Tang X, Xu D: Transplantation Proc 30:3573, 1998