Pharmacokinetics and tolerance of mycophenolate mofetil in renal transplant children

Abstract

Mycophenolate mofetil (MMF) is a prodrug that is hydrolyzed to the active immunosuppressant mycophenolic acid (MPA). The drug is now widely prescribed for adult renal transplant recipients and its use has been extended to pediatric patients, although pharmacological data in this age group are limited. Nine pediatric renal transplant recipients received MMF with corticosteroids and either cyclosporine or tacrolimus a median of 55 months (range 7.5-124 months) months after transplantation. The pharmacokinetic parameters of MPA and MPA glucuronide (MPAG) were determined at steady state by high-performance liquid chromatography after administration of MMF at the oral dose of 494+/-142 mg/m(2) twice daily. MPA was rapidly absorbed, with a peak concentration at 1.4 h. The mean plasma concentration of MPA at steady state was 4.7+/-1.3 microg/ml. The areas under the plasma concentration-time curves (AUCs) over 12 h (between two administrations) were 57.0+/-15.3 microg.h/ml for MPA and 1,515+/-722 microg.h/ml for MPAG, and the apparent oral clearance was 11.7+/-7.0 and 0.5+/-0.4 l/h for MPA and MPAG, respectively. Assuming that the pharmacokinetics of MPA was dose dependent, the mean concentration at steady state and the AUC for MPA were calculated for the recommended dosage schedule of 600 mg/m(2) every 12 h and were 6.3+/-2.7 microg/ml and 75.2+/-32.9 microg.h/ml, respectively. The tolerance of MMF was studied prospectively with a follow-up of 1.1+/-0.2 years. Gastrointestinal disorders requiring dosage reduction or discontinuation of therapy, observed in five of nine patients, occurred at an incidence higher than expected from adult data. Our results suggest that the dose of 600 mg/m(2) every 12 h extrapolated from adult data for use in pediatric patients would be associated with plasma levels and AUCs higher than expected and may be associated with a higher incidence of side-effects, primarily gastrointestinal.

Human Udp-Glucuronosyltransferases Show Atypical Metabolism of Mycophenolic Acid and Inhibition by Curcumin

“…Although 1A10 deviated significantly from linearity, there is no evidence that MPA exhibited cooperative effects on its activity. Hence, the capacity of MPA to show such an increase by four isozymes no doubt contributes to its high level of glucuronide production in vivo (Ding et al, 1993;Jacqz-Aigrain et al, 2000). Although MPA is highly prescribed because of its highly selective inhibition of IMPDH II and other beneficial effects (Transplantation Study Group, 1996), its extensive metabolism to glucuronides (Ding et al, 1993;Shütz et al, 1999;Jacqz-Aigrain et al, 2000), no doubt, contributes to high glucuronide accumulation in patient blood, which evidently compromises the efficacy of immunosuppression by MPA.…”

“…Hence, the capacity of MPA to show such an increase by four isozymes no doubt contributes to its high level of glucuronide production in vivo (Ding et al, 1993;Jacqz-Aigrain et al, 2000). Although MPA is highly prescribed because of its highly selective inhibition of IMPDH II and other beneficial effects (Transplantation Study Group, 1996), its extensive metabolism to glucuronides (Ding et al, 1993;Shütz et al, 1999;Jacqz-Aigrain et al, 2000), no doubt, contributes to high glucuronide accumulation in patient blood, which evidently compromises the efficacy of immunosuppression by MPA. Both MPAG and AcMPAG (M2) were observed at high concentrations in the plasma of transplant recipients receiving mycophenolate mofetil Wieland et al, 2000), which indicates that our results are consistent with reports that found AcMPAG in humans.…”

“…Despite its high dose requirement with attendant side effects, it is widely prescribed for renal transplant recipients (Jacqz-Aigrain et al, 2000;MacPhee et al, 2000) because of its many desirable properties (Allison and Eugui, 2000). This fungal-derived agent has become a desirable and important drug that is administered alone or in combination to immunosuppress cytotoxic T-lymphocyte proliferation and chronic allograft dysfunction following solid-organ transplantation.…”

Mikofenolat Mofetil sebagai Terapi Sindrom Nefrotik Relaps Sering dan Resisten Steroid pada Anak

“…19 Jacqz-Aigrain dkk. 2000 melaporkan pada 9 anak berumur (8,2 + 3,5) tahun, 16 Bunchman dkk. 2001 melaporkan pada 100 anak berumur 3 bulan -18 tahun, 21 dan DavidNeto dkk.…”

“…Pada 1 pasien terjadi anoreksia berat, penurunan berat badan, diare, dan pada 4 pasien terjadi nyeri abdomen yang mengalami perbaikan setelah dosis dikurangi atau obat dihentikan. 16 Filler dkk. 2003 melaporkan diare pada 1/15.…”