UNEXPECTED AUGMENTATION OF MYCOPHENOLIC-ACID PHARMACOKINETICS IN RENAL-TRANSPLANT PATIENTS RECEIVING TACROLIMUS AND MYCOPHENOLATE MOFETIL IN COMBINATION THERAPY, AND ANALOGOUS IN-VITRO FINDINGS
K. Zucker et al., UNEXPECTED AUGMENTATION OF MYCOPHENOLIC-ACID PHARMACOKINETICS IN RENAL-TRANSPLANT PATIENTS RECEIVING TACROLIMUS AND MYCOPHENOLATE MOFETIL IN COMBINATION THERAPY, AND ANALOGOUS IN-VITRO FINDINGS, Transplant immunology, 5(3), 1997, pp. 225-232
Mycophenolate mofetil (MMF) a potent immunosuppressive agent, has rece
ntly been approved for clinical use (CellCept(TM)) in renal transplant
patients in combination with cyclosporine (CsA). With the expanded us
e of tacrolimus (Prograf(TM)) as well in renal transplant patients, th
ere is a lack of pharmacokinetic studies clarifying drug interactions
between the three agents. A pharmacokinetic study was performed on 18
stable renal transplant patients receiving MMF and tacrolimus together
, and four control groups, one receiving tacrolimus alone, two receivi
ng CsA, in combination with MMF (1.0 or 1.5 g bid), and one receiving
CsA microemulsion (Neoral(TM)). Area-under-the-curve values were calcu
lated for each drug to assess if there was a reciprocal effect on the
respective bioavailability of each. In vitro, the immunosuppressive ef
fect of trough level plasma from each patient group was studied using
mixed lymphocyte culture (MLC), as well as MLC reactions spiked with v
arious combinations of each drug. There was a minimal effect of MMF on
tacrolimus pharmacokinetics. However, patients receiving tacrolimus a
nd MMF displayed significantly higher levels (C-min and area under the
curve) of mycophenolic acid (MPA) than those receiving CsA (Sandimmun
e(TM) or Neoral(TM)) and the same dose of MMF (50.2 +/- 16.5 vs 32.1 /- 16.7 mu g h/ml AUC, p < 0.02). Equivalent MPA levels could be attai
ned in patients receiving CsA if the MMF dose was increased by 50% (1.
5 g bid). There were also significantly lower levels of the glucuronid
e metabolite of MPA (MPAG) (755 +/- 280 vs 1230 +/- 250 mu g h/ml AUC,
p = 0.02), suggesting a specific inhibition (either direct or indirec
t) of the conversion of MPA to MPAG in tacrolimus patients, as opposed
io those receiving CsA. For each drug combination, there was a positi
ve correlation between the plasma immunosuppressive effect seen in MLC
assays and the MMF dose. In addition, trough plasma from patients rec
eiving tacrolimus and MMF was significantly more MLC inhibitory than f
rom those receiving CsA or CsA microemulsion and equivalent-dose MMF.
Culture media containing MPA and tacrolimus equal to clinical therapeu
tic trough concentrations (10 ng/ml) were significantly more MLC inhib
itory than CsA at equivalent clinical therapeutic trough concentration
s (200 ng/ml) with equivalent MPA levels. These studies in renal trans
plant patients suggest that tacrolimus in combination with MMF may res
ult in a greater degree of immunosuppression than may be anticipated.