Pharmacokinetics and variability of mycophenolic acid from enteric-coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients

Manfred Hummel, Nizar Yonan, Heather Ross, Leslie W. Miller, Romain Sechaud, Sebastien Balez, Ernst Ulrich Koelle, Gino Gerosa, K. Aaronson, L. Ahualli, L. Almenar, J. M. Arizon, G. Arpesella, M. G. Crespo, S. F. David, J. Butler, T. Dengler, J. Egan, H. J. Eisen, J. HaddadR. Davies, A. M. Keogh, J. Kobashigawa, H. B. Lehmkuhl, R. Hetzer, U. Livi, D. Modry, J. Burton, G. M. Mullen, B. Pisani, A. J. Murday, D. G. Renlund, J. Segovia, L. Alonso-Pulpon, S. Perrone, M. Vigano, M. J. Zucker

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33 Scopus citations


ComparativeDrug:Mycophenolate mofetil (Cell-Cept): 1500 mg bid (=3000 mg daily); single doses were 125-1500 mg (=1625 mg daily), 250-1500 mg (=1750 mg daily), and 1500 mg daily at weeks 2, 12 , and 52 respectively. Duration: up to 52 weeks.

Results:Mean CsA levels, which were not different between EC-Myfortic and MMF groups, increased within the first 2 weeks posttransplantation and remained constant thereafter. For both EC-Myfortic and MMF groups, systemic exposure to MPA increased from weeks 2 to 12. AUCτ,ss at week 52 were comparable with values at week 12. Following EC-Myfortic, systemic MPAG exposure increased with time. Because of high inter-individual variability at week 2, this trend was not evident for the MMF group. Because of the enteric-coating of Myfortic, MPA Cmax,ss occurred 1 hour later (tmax) compared with MMF at all assessments (2.0-2.5 hours vs. 0.8-0.9 hours). In terms of systemic exposure to MPA and MPAG, similar results were obtained for both treatments. AUCτ,ss, Cmax,ss, and Cmin,ss were not significantly different between the 2 groups at any of the weeks (p=0.225 to 0.990). %PTF were comparable in both groups, whereas the MPAG plasma concentration fluctuations were considerably lower compared with MPA. Inter-subject variabilities (percent coefficient of variation, %CV) in MPA Pk were high and comparable in both EC-Myfortic and MMF groups, while intra-subject variabilities were numerically smaller with EC-Myfortic. For EC-Myfortic, the intra-subject %CVs for MPA AUCτ,ss, Cmax,ss, and Cmin,ss were 28%, 63%, and 34%, respectively (vs. 54%, 139%, and 41%, respectively, with MMF). The intra-subject variabilities for MPAG AUCτ,ss, Cmax,ss,and Cmin,ss were 37%, 36%, and 52% with EC-Myfortic vs. 51%, 47%, and 63% with MMF, respectively.

AdverseEffects:No adverse events were mentioned.

AuthorsConclusions:In conclusion, for de novo heart transplant recipients a dose of EC-MPS [mycophenolate sodium] 1080 mg bid in combination with cyclosporine appears appropriate to deliver an adequate systemic MPA exposure, comparable with MMF 1500 mg bid. Overall, there is a large inter- and intra-subject variability in MPA pharmacokinetics in this patient population with both treatments.

FreeText:Steady-state Pk profiles of MPA and MPAG were assessed on week 2, week 12, and week 52. Tests: plasma MPA and MPAG (high performance liquid chromatography with ultraviolet detection or liquid chromatography/mass spectrometry) and serum cyclosporine A (CsA) level. Pk parameters: highest measured plasma concentration (Cmax,ss), and corresponding time (tmax,ss), minimum plasma concentration at steady-state (Cmin,ss), area under the concentration-time curve during a dosing interval (AUCτ,ss), and peak trough fluctuation (PTF). Concomitant drug was CsA microemulsion.

Indications:Graft rejection prophylaxis in 17 patients undergoing heart transplantation.

Patients:32 patients, 25 male and 7 female, mean age 49.8 years. EC-Myfortic group: 17 patients. MMF group: 15 patients.

TypeofStudy:This study evaluated the within-formulation temporal changes in the steady-state pharmacokinetics of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) and compared the pharmacokinetic (Pk) parameters and within- and between-subject Pk variabilities between enteric-coated (EC)-Myfortic and mycophenolate mofetil (MMF). A substudy performed within a multicenter, controlled, single-blind, randomized, comparative clinical trial investigating the efficacy of and safety of EC-Myfortic and MMF among de novo heart transplant recipients.

DosageDuration:1080 mg bid (=2160 mg daily); single doses were 540-1080 mg (=1620 mg daily), 180-1080 mg (=1260 mg daily), and 1080 mg daily at weeks 2, 12 , and 52 respectively. Duration: up to 52 weeks.

Original languageEnglish (US)
Pages (from-to)18-23
Number of pages6
JournalClinical Transplantation
Issue number1
StatePublished - Jan 1 2007

All Science Journal Classification (ASJC) codes

  • Transplantation


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