© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 783–788 DOI: 10.1111/ctr.12379
Clinical Transplantation
Gastrointestinal side effects in liver transplant recipients taking enteric-coated mycophenolate sodium vs. mycophenolate mofetil Lopez-Solis R, DeVera M, Steel J, Fedorek S, Sturdevant M, Hughes C, Humar A. Gastrointestinal side effects in liver transplant recipients taking enteric-coated mycophenolate sodium vs. mycophenolate mofetil. Abstract: In the setting of liver transplantation, mycophenolate mofetil (MMF) may be used as an adjuvant therapy for immunosuppression to prevent graft rejection; however, its use may be limited due to severe gastrointestinal (GI) side effects. In contrast, enteric-coated mycophenolate sodium (EC-MPS) may be associated with less severe side effects and hence better tolerability. We compared the side effects of EC-MPS to MMF in liver transplant patients in a de novo study (Study I —randomized, prospective, double-blinded) and a conversion study (Study II). In both studies, the severity of GI symptoms was assessed at various time points using the Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation). In Study I, the symptoms of 30 recipients receiving EC-MPS (n = 15) were compared to 15 recipients receiving MMF. A multivariate analysis of variance (MANOVA) of the total GSRS scores and symptom syndrome subscores revealed no significant difference (p > 0.05) between the two medications over time. A conversion study (Study II) with 29 participants, however, showed that over time, all GI symptoms improved significantly (p < 0.001) when the patients were treated with EC-MPS instead of MMF.
Roberto Lopez-Solisa, Michael DeVerab, Jennifer Steela, Sheila Fedoreka, Mark Sturdevanta, Christopher Hughesa and Abhinav Humara a
Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA and bLoma Linda Transplant Center, Loma Linda University Medical Center, Loma Linda, CA, USA Key words: enteric-coated – mycophenolate sodium – mycophenolate mofetil – Gastrointestinal Symptoms Rating Scale – immunosuppression – liver transplantation Corresponding author: Roberto C. Lopez, MD, University of Pittsburgh Department of Surgery, UPMC Montefiore, 3459 Fifth Avenue- 7 South, Pittsburgh, PA 15213, USA. Tel.: 412 383 7228; fax: 412 647 5480; e-mail: [email protected] Conflict of interest: None. Accepted for publication 16 April 2014
Liver transplantation (LTx) is the only life-saving treatment for end-stage liver disease. Advances in surgical technique as well as intra- and post-operative care in the past decade have markedly improved patient and allograft survival. Newer and more potent immunosuppressive agents have also been introduced, significantly decreasing the incidence of rejection and contributing to the long-term success of LTx (1). However, this success has come at a price. The majority of posttransplantation complications, such as infections, malignancies, renal failure, and the exacerbation or precipitation of chronic diseases (e.g., hypertension, diabetes) are a direct consequence of immunosuppression. Currently, there is no consensus on an optimal immunosuppressive protocol
following LTx, but the agents most commonly used in transplant centers worldwide are calcineurin inhibitors (CNIs), chiefly tacrolimus and cyclosporine. These drugs are typically used in conjunction with other agents to either decrease their side effects or to potentiate the overall level of immunosuppression. Examples of these “adjuvant” agents include mycophenolate mofetil, MMF, (CellCeptâ, Genentech USA, Inc., South San Francisco, CA, USA), sirolimus, and steroids. CellCeptâ is an FDA-approved immunosuppressive drug widely used in LTx patients (2–4). One of the indications for its addition is to decrease the renal and/or neurologic side effects of CNIs. Enteric-coated mycophenolate sodium (EC-MPS) is a formulation of mycophenolic acid (MPA) that
783
Lopez-Solis et al.
releases an active molecule in the intestine that has a similar efficacy and side effect profile to MMF when used after kidney transplantation (5– 7). MMF has almost completely replaced the purinic agonist azathioprine in the immunosuppresive therapy of transplant recipients. MPA, the active metabolite of MMF, reversibly inhibits inosine 5-monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo pathway of purine synthesis. Whereas other cell types can utilize the salvage pathway for purine synthesis, lymphocytes are wholly dependent on de novo purine synthesis for their proliferation. Therefore, MPA has potent cytostatic effects on these cells. Despite its efficacy, therapy with MMF is limited by GI tolerability (8). EC-MPS (Myfortic, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) was developed to minimize these side effects. Pharmacokinetic studies have shown that EC-MPS and MMF at bioequivalent doses yield a comparable exposition to MPA (area under the curve), but EC-MPS yields an 11% lower peak plasma concentration (Cmax) and a more variable time to reach peak plasma concentration (Tmax). Pharmacokinetic and pharmacodynamics studies have shown that despite the different Cmaxes, there is no difference in inosine-50 -monophosphate dehydrogenase inhibition between equimolar doses of MMF and ECMPS (9, 10). The main reason for beginning someone on adjuvant MMF therapy is to decrease CNI doses to alleviate the CNI side effects of neurotoxicity and nephrotoxicity while keeping a sufficiently high level of immunosuppression. MMF’s use as an adjuvant treatment remains limited, however, in light of its GI side effects and bone marrow suppression. The primary motivation for this study was to determine whether EC-MPS offers more tolerable GI side effects than MMF; an improved side effect profile would lead to increased drug compliance, and a lower dose of CNI if used in conjunction with EC-MPS to achieve better immunosuppressant coverage. The Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation), was used to assess the severity of the GI symptoms at various points (11–13). Patients and methods
This investigation was a prospective, single-center trial divided into two different studies: Study I (the de novo investigation) was a prospective, ran-
784
domized double-blinded trial where adult LTx recipients were treated with either MMF or ECMPS for 12 wk and their GI symptoms recorded and compared at various time points using the GSRS questionnaire. Study II (the conversion investigation) was a prospective study where adult LTx recipients that were initially treated with MMF were switched to EC-MPS for 12 wk to see whether their GI symptoms improved compared to their baseline with MMF. Patients eligible for inclusion in both arms of the investigation were those that were enrolled in the Thomas Starzl Transplantation Institute at the University of Pittsburgh during the time period beginning in December 2006 and ending in June 2009; these were patients that had received liver transplants from deceased donors and were adults between the ages of 18–80 yr at the time of screening. Exclusion criteria included the following: recipients of multi-organ transplants; HIV-positive status; living liver grafts (which require a different immunosuppressive regimen); pregnancy (subjects underwent pregnancy tests prior to inclusion in the study); breast feeding; history of extrahepatic malignancy within the last five yr (except excised squamous or basal cell carcinoma of the skin); thrombocytopenia (
Clin Transplant 2014: 28: 783–788 DOI: 10.1111/ctr.12379
Clinical Transplantation
Gastrointestinal side effects in liver transplant recipients taking enteric-coated mycophenolate sodium vs. mycophenolate mofetil Lopez-Solis R, DeVera M, Steel J, Fedorek S, Sturdevant M, Hughes C, Humar A. Gastrointestinal side effects in liver transplant recipients taking enteric-coated mycophenolate sodium vs. mycophenolate mofetil. Abstract: In the setting of liver transplantation, mycophenolate mofetil (MMF) may be used as an adjuvant therapy for immunosuppression to prevent graft rejection; however, its use may be limited due to severe gastrointestinal (GI) side effects. In contrast, enteric-coated mycophenolate sodium (EC-MPS) may be associated with less severe side effects and hence better tolerability. We compared the side effects of EC-MPS to MMF in liver transplant patients in a de novo study (Study I —randomized, prospective, double-blinded) and a conversion study (Study II). In both studies, the severity of GI symptoms was assessed at various time points using the Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation). In Study I, the symptoms of 30 recipients receiving EC-MPS (n = 15) were compared to 15 recipients receiving MMF. A multivariate analysis of variance (MANOVA) of the total GSRS scores and symptom syndrome subscores revealed no significant difference (p > 0.05) between the two medications over time. A conversion study (Study II) with 29 participants, however, showed that over time, all GI symptoms improved significantly (p < 0.001) when the patients were treated with EC-MPS instead of MMF.
Roberto Lopez-Solisa, Michael DeVerab, Jennifer Steela, Sheila Fedoreka, Mark Sturdevanta, Christopher Hughesa and Abhinav Humara a
Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA and bLoma Linda Transplant Center, Loma Linda University Medical Center, Loma Linda, CA, USA Key words: enteric-coated – mycophenolate sodium – mycophenolate mofetil – Gastrointestinal Symptoms Rating Scale – immunosuppression – liver transplantation Corresponding author: Roberto C. Lopez, MD, University of Pittsburgh Department of Surgery, UPMC Montefiore, 3459 Fifth Avenue- 7 South, Pittsburgh, PA 15213, USA. Tel.: 412 383 7228; fax: 412 647 5480; e-mail: [email protected] Conflict of interest: None. Accepted for publication 16 April 2014
Liver transplantation (LTx) is the only life-saving treatment for end-stage liver disease. Advances in surgical technique as well as intra- and post-operative care in the past decade have markedly improved patient and allograft survival. Newer and more potent immunosuppressive agents have also been introduced, significantly decreasing the incidence of rejection and contributing to the long-term success of LTx (1). However, this success has come at a price. The majority of posttransplantation complications, such as infections, malignancies, renal failure, and the exacerbation or precipitation of chronic diseases (e.g., hypertension, diabetes) are a direct consequence of immunosuppression. Currently, there is no consensus on an optimal immunosuppressive protocol
following LTx, but the agents most commonly used in transplant centers worldwide are calcineurin inhibitors (CNIs), chiefly tacrolimus and cyclosporine. These drugs are typically used in conjunction with other agents to either decrease their side effects or to potentiate the overall level of immunosuppression. Examples of these “adjuvant” agents include mycophenolate mofetil, MMF, (CellCeptâ, Genentech USA, Inc., South San Francisco, CA, USA), sirolimus, and steroids. CellCeptâ is an FDA-approved immunosuppressive drug widely used in LTx patients (2–4). One of the indications for its addition is to decrease the renal and/or neurologic side effects of CNIs. Enteric-coated mycophenolate sodium (EC-MPS) is a formulation of mycophenolic acid (MPA) that
783
Lopez-Solis et al.
releases an active molecule in the intestine that has a similar efficacy and side effect profile to MMF when used after kidney transplantation (5– 7). MMF has almost completely replaced the purinic agonist azathioprine in the immunosuppresive therapy of transplant recipients. MPA, the active metabolite of MMF, reversibly inhibits inosine 5-monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo pathway of purine synthesis. Whereas other cell types can utilize the salvage pathway for purine synthesis, lymphocytes are wholly dependent on de novo purine synthesis for their proliferation. Therefore, MPA has potent cytostatic effects on these cells. Despite its efficacy, therapy with MMF is limited by GI tolerability (8). EC-MPS (Myfortic, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) was developed to minimize these side effects. Pharmacokinetic studies have shown that EC-MPS and MMF at bioequivalent doses yield a comparable exposition to MPA (area under the curve), but EC-MPS yields an 11% lower peak plasma concentration (Cmax) and a more variable time to reach peak plasma concentration (Tmax). Pharmacokinetic and pharmacodynamics studies have shown that despite the different Cmaxes, there is no difference in inosine-50 -monophosphate dehydrogenase inhibition between equimolar doses of MMF and ECMPS (9, 10). The main reason for beginning someone on adjuvant MMF therapy is to decrease CNI doses to alleviate the CNI side effects of neurotoxicity and nephrotoxicity while keeping a sufficiently high level of immunosuppression. MMF’s use as an adjuvant treatment remains limited, however, in light of its GI side effects and bone marrow suppression. The primary motivation for this study was to determine whether EC-MPS offers more tolerable GI side effects than MMF; an improved side effect profile would lead to increased drug compliance, and a lower dose of CNI if used in conjunction with EC-MPS to achieve better immunosuppressant coverage. The Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation), was used to assess the severity of the GI symptoms at various points (11–13). Patients and methods
This investigation was a prospective, single-center trial divided into two different studies: Study I (the de novo investigation) was a prospective, ran-
784
domized double-blinded trial where adult LTx recipients were treated with either MMF or ECMPS for 12 wk and their GI symptoms recorded and compared at various time points using the GSRS questionnaire. Study II (the conversion investigation) was a prospective study where adult LTx recipients that were initially treated with MMF were switched to EC-MPS for 12 wk to see whether their GI symptoms improved compared to their baseline with MMF. Patients eligible for inclusion in both arms of the investigation were those that were enrolled in the Thomas Starzl Transplantation Institute at the University of Pittsburgh during the time period beginning in December 2006 and ending in June 2009; these were patients that had received liver transplants from deceased donors and were adults between the ages of 18–80 yr at the time of screening. Exclusion criteria included the following: recipients of multi-organ transplants; HIV-positive status; living liver grafts (which require a different immunosuppressive regimen); pregnancy (subjects underwent pregnancy tests prior to inclusion in the study); breast feeding; history of extrahepatic malignancy within the last five yr (except excised squamous or basal cell carcinoma of the skin); thrombocytopenia (
