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Mycophenolic Acid Reaches Therapeutic Levels Whereas Mycophenolate Mofetil Does Not
Mycophenolic Acid Reaches Therapeutic Levels Whereas Mycophenolate Mofetil Does Not R. Vilalta Casas, Á. Vila López, J.L. Nieto Rey, L.E. Lara Moctezuma, Á. Madrid Aris, M. Quintana Montero, and L. Pou Clave ABSTRACT Background. In kidney transplanted children, it is difficult to obtain blood levels of mycophenolic acid between 2 and 4 g/mL, when mycophenolate mofetil doses up to 30 mg/kg/d are given two or three times a day. We proposed that using mycophenolic acid, instead of the salt mycophenolate mofetil, may help us to reach target levels. Aim. We sought to describe the pharmacokinetics of mycophenolic acid in eight kidney transplanted children over a period of 1.2 ⫾ 0.8 years. Patients and methods. Eight patients (5 boys and 3 girls) aged 7.0 ⫾ 1.8 years received cadaveric kidney transplantations. Induction with basiliximab was followed by cyclosporine (n ⫽ 4) or tacrolimus (n ⫽ 4), tapered steroids (withdrawal at 12 months in six cases and maintained at 0.15 mg/kg/d in two cases), and mycophenolate mofetil (25 to 30 mg/kg/d two or three times a day). For 1.0 ⫾ 0.3 years mycophenolic acid levels were between 0.8 ⫾ 0.3 g/mL. When mycophenolic acid sodium tablets were available, all patients were switched to this drug. Results. After the conversion, blood levels obtained at 8 ⫾ 3 days were 1.5 to 5.0 g/mL (median, 3.2), which were far closer to the target 2 to 4 g/mL. No gastrointestinal disorders were observed with the follow-up of 72 ⫾ 18 days. Conclusion. Mycophenolic acid sodium reaches therapeutic levels whereas mycophenolate mofetil does not. If mycophenolic acid were available in syrup form, it could be used in patients under 5 years of age. It is necessary to follow these patients to rule out enzymatic induction.
K
IDNEY TRANSPLANTATION is the treatment of choice for children with end-stage renal disease. Patients with well-functioning grafts have a good quality of life with near-normal growth. Despite recent advances, it is difficult to tailor immunosuppressive regimens in small children, because attained blood levels are different from those obtained in adult patients treated with the same dose per body weight. This is particularly true upon the addition of mycophenolate mofetil (MMF) to calcineurin inhibitor– based regimens in children. Interindividual variability and potential drug– drug interactions make the systemic exposure of mycophenolic acid (MPA) in children unpredictable using a fixed-dose regime. A sustained level of MPA in plasma significantly correlates with a decreased likelihood of an acute rejection episode after kidney transplantation.1 In kidney transplanted children, it is difficult to obtain blood levels of MPA between 2 and 4 g/mL, the level recom-
mended in adults,2 even if MMF doses up to 30 mg/kg/d are given two or three times a day. We postulated that the use of enteric-coated mycophenolate sodium (EC-MPS, Myfortic) in place of the salt MMF would help us to reach target levels.3 We sought to describe MPA blood levels among eight stable kidney-transplanted children before (first period) versus after (second period) the administration of entericcoated mycophenolate sodium (EC-MPS, Myfortic) at an From the Pediatric Nephrology Department, (R.V.C., A.V.L., J.L.N.R., L.E.L.M., A.M.A., M.Q.M.), and the Laboratory of Pharmacology (L.P.C.), Vall d’Hebron Hospital, Barcelona, Spain. Address reprint requests to Dr Ramon Vilalta Casas, Pediatric Nephrology Department, Vall d’Hebron Hospital, Passeig Vall dHebron 119-129, Barcelona 08035, Spain. E-mail: rvilalta@ vhebron.net
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.08.062
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2400
Transplantation Proceedings, 38, 2400 –2401 (2006)
MYCOPHENOLIC ACID
approximate dose level of 450 mg/m2 body surface area over a period of 1.2 ⫾ 0.8 years. We evaluated the safety and tolerability of EC-MPS in this pediatric population. PATIENTS AND METHODS Eight patients (5 boys and 3 girls) aged 7.0 ⫾ 1.8 years received a cadaveric kidney transplant. Induction with basiliximab was followed by cyclosporine or tacrolimus (4 patients cyclosporine, 4 patients tacrolimus), tapered steroids (withdrawal at 12 months in six cases and maintained at 0.15 mg/kg/d in two), and for all patients, MMF (25 to 30 mg/kg/d two or three times a day). In the first period of 0.8 ⫾ 0.3 years, the achieved MPA levels were 0.8 ⫾ 0.3 g/mL, which were always below the range of 2 to 4 g/mL recommended in adults. When EC-MPS tablets were available, all the children were switched to this formulation.
RESULTS
After the substitution (second period), blood levels of MPA were 1.5 to 5.0 g/mL (median, 3.2), within 8 ⫾ 3 days, which was closer to the target range of 2 to 4 g/mL. No gastrointestinal disorders were observed during a follow-up of 172 ⫾ 18 days. We did not observe any differences between the cyclosporine or tacrolimus regimens.
2401
DISCUSSION
In our patients, EC-MPS treatment achieved therapeutic levels of MPA whereas MMF did not. There were no differences between the cyclosporine or tacrolimus regimens or special interactions with cyclosporine, as others have reported.4 If EC-MPS were available in smaller doses, it could be used in patients ⬍5 years of age. It is necessary to follow these patients to exclude enzyme induction and a reduction in concentrations to low levels.
REFERENCES 1. Ettenger R, Sarwal MM: Mycophenolate mofetil in pediatric renal transplantation. Transplantation 80(2 Suppl):S272, 2005 2. Van Gelder T, Shaw LM: The rationale for and limitations of therapeutic drug monitoring for mycophenolate mofetil in transplantation. Transplantation 80(2 Suppl):S244, 2005 3. Ettenger R, Bartosh S, Choi L, et al: Pharmacokinetics of enteric coated mycophenolate sodium in stable pediatric renal transplant recipients. Pediatric Transplant 9:780, 2005 4. Ghio L, Ferraresso M, Vigano SM, et al: Mycophenolate mofetil pharmacokinetic monitoring in pediatric kidney transplant recipients. Transplant Proc 37:856, 2005
K
IDNEY TRANSPLANTATION is the treatment of choice for children with end-stage renal disease. Patients with well-functioning grafts have a good quality of life with near-normal growth. Despite recent advances, it is difficult to tailor immunosuppressive regimens in small children, because attained blood levels are different from those obtained in adult patients treated with the same dose per body weight. This is particularly true upon the addition of mycophenolate mofetil (MMF) to calcineurin inhibitor– based regimens in children. Interindividual variability and potential drug– drug interactions make the systemic exposure of mycophenolic acid (MPA) in children unpredictable using a fixed-dose regime. A sustained level of MPA in plasma significantly correlates with a decreased likelihood of an acute rejection episode after kidney transplantation.1 In kidney transplanted children, it is difficult to obtain blood levels of MPA between 2 and 4 g/mL, the level recom-
mended in adults,2 even if MMF doses up to 30 mg/kg/d are given two or three times a day. We postulated that the use of enteric-coated mycophenolate sodium (EC-MPS, Myfortic) in place of the salt MMF would help us to reach target levels.3 We sought to describe MPA blood levels among eight stable kidney-transplanted children before (first period) versus after (second period) the administration of entericcoated mycophenolate sodium (EC-MPS, Myfortic) at an From the Pediatric Nephrology Department, (R.V.C., A.V.L., J.L.N.R., L.E.L.M., A.M.A., M.Q.M.), and the Laboratory of Pharmacology (L.P.C.), Vall d’Hebron Hospital, Barcelona, Spain. Address reprint requests to Dr Ramon Vilalta Casas, Pediatric Nephrology Department, Vall d’Hebron Hospital, Passeig Vall dHebron 119-129, Barcelona 08035, Spain. E-mail: rvilalta@ vhebron.net
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.08.062
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2400
Transplantation Proceedings, 38, 2400 –2401 (2006)
MYCOPHENOLIC ACID
approximate dose level of 450 mg/m2 body surface area over a period of 1.2 ⫾ 0.8 years. We evaluated the safety and tolerability of EC-MPS in this pediatric population. PATIENTS AND METHODS Eight patients (5 boys and 3 girls) aged 7.0 ⫾ 1.8 years received a cadaveric kidney transplant. Induction with basiliximab was followed by cyclosporine or tacrolimus (4 patients cyclosporine, 4 patients tacrolimus), tapered steroids (withdrawal at 12 months in six cases and maintained at 0.15 mg/kg/d in two), and for all patients, MMF (25 to 30 mg/kg/d two or three times a day). In the first period of 0.8 ⫾ 0.3 years, the achieved MPA levels were 0.8 ⫾ 0.3 g/mL, which were always below the range of 2 to 4 g/mL recommended in adults. When EC-MPS tablets were available, all the children were switched to this formulation.
RESULTS
After the substitution (second period), blood levels of MPA were 1.5 to 5.0 g/mL (median, 3.2), within 8 ⫾ 3 days, which was closer to the target range of 2 to 4 g/mL. No gastrointestinal disorders were observed during a follow-up of 172 ⫾ 18 days. We did not observe any differences between the cyclosporine or tacrolimus regimens.
2401
DISCUSSION
In our patients, EC-MPS treatment achieved therapeutic levels of MPA whereas MMF did not. There were no differences between the cyclosporine or tacrolimus regimens or special interactions with cyclosporine, as others have reported.4 If EC-MPS were available in smaller doses, it could be used in patients ⬍5 years of age. It is necessary to follow these patients to exclude enzyme induction and a reduction in concentrations to low levels.
REFERENCES 1. Ettenger R, Sarwal MM: Mycophenolate mofetil in pediatric renal transplantation. Transplantation 80(2 Suppl):S272, 2005 2. Van Gelder T, Shaw LM: The rationale for and limitations of therapeutic drug monitoring for mycophenolate mofetil in transplantation. Transplantation 80(2 Suppl):S244, 2005 3. Ettenger R, Bartosh S, Choi L, et al: Pharmacokinetics of enteric coated mycophenolate sodium in stable pediatric renal transplant recipients. Pediatric Transplant 9:780, 2005 4. Ghio L, Ferraresso M, Vigano SM, et al: Mycophenolate mofetil pharmacokinetic monitoring in pediatric kidney transplant recipients. Transplant Proc 37:856, 2005