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

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.