A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Cellcept Pharmacology, Pharmacokinetics, Studies, Metabolism - Mycophenolate Mofetil
Cellcept Pharmacology, Pharmacokinetics, Studies, Metabolism - Mycophenolate Mofetil
CLINICAL PHARMACOLOGY
Mechanism of Action
Mycophenolate mofetil has been demonstrated in experimental animal models
to prolong the survival of allogeneic transplants (kidney, heart, liver,
intestine, limb, small bowel, pancreatic islets, and bone marrow).
Mycophenolate mofetil has also been shown to reverse ongoing acute rejection
in the canine renal and rat cardiac allograft models. Mycophenolate mofetil
also inhibited proliferative arteriopathy in experimental models of aortic
and heart allografts in rats, as well as in primate cardiac xenografts.
Mycophenolate mofetil was used alone or in combination with other immunosuppressive
agents in these studies. Mycophenolate mofetil has been demonstrated to
inhibit immunologically-mediated inflammatory responses in animal models
and to inhibit tumor development and prolong survival in murine tumor
transplant models.
Mycophenolate mofetil is rapidly absorbed following oral administration
and hydrolyzed to form MPA, which is the active metabolite. MPA is a potent,
selective, uncompetitive, and reversible inhibitor of inosine monophosphate
dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine
nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes
are critically dependent for their proliferation on de novo synthesis
of purines whereas other cell types can utilize salvage pathways, MPA
has potent cytostatic effects on lymphocytes. MPA inhibits proliferative
responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation.
Addition of guanosine or deoxyguanosine reverses the cytostatic effects
of MPA on lymphocytes. MPA also suppresses antibody formation by B-lymphocytes.
MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins
that are involved in intercellular adhesion to endothelial cells and may
inhibit recruitment of leukocytes into sites of inflammation and graft
rejection. Mycophenolate mofetil did not inhibit early events in the activation
of human peripheral blood mononuclear cells, such as the production of
interleukin-1(IL-1) and interleukin-2(IL-2), but did block the coupling
of these events to DNA synthesis and proliferation.
Pharmacokinetics
Following oral and IV administration, mycophenolate mofetil undergoes
rapid and complete metabolism to MPA, the active metabolite. Oral absorption
of the drug is rapid and essentially complete. MPA is metabolized to form
the phenolic glucuronide of MPA (MPAG) which is not pharmacologically
active. The parent drug, mycophenolate mofetil, can be measured systemically
during the intravenous infusion; however, shortly (about 5 minutes) after
the infusion is stopped or after oral administration, MMF concentration
is below the limit of quantitation (0.4 µg/mL).
Absorption: In 12 healthy volunteers, the mean absolute
bioavailability of oral mycophenolate mofetil relative to IV mycophenolate
mofetil (based on MPA AUC) was 94%. The area under the plasma-concentration
time curve (AUC) for MPA appears to increase in a dose-proportional fashion
in renal transplant patients receiving multiple doses of mycophenolate
mofetil up to a daily dose of 3 g (see table below on pharmacokinetic
parameters in renal and cardiac transplant patients).
The Cmax and AUC of MPA in early transplant patients (<40
days posttransplant) are approximately 45% to 50% and 20% to 30% lower,
respectively, as compared to healthy volunteers or to stable renal and
cardiac transplant patients.
Food (27 g fat, 650 calories) had no effect on the extent of absorption
MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g
bid to renal transplant patients. However, MPA Cmax was decreased
by 40% in the presence of food (see DOSAGE
AND ADMINISTRATION).
Distribution: The mean (± SD) apparent volume of distribution
of MPA in 12 healthy volunteers is approximately 3.6 (+ 1.5) and 4.0 (+
1.2) L/kg following IV and oral administration, respectively. MPA, at
clinically relevant concentrations, is 97% bound to plasma albumin. MPAG
is 82% bound to plasma albumin at MPAG concentration ranges that are normally
seen in stable renal transplant patients; however, at higher MPAG concentrations
(observed in patients with renal impairment or delayed graft function),
the binding of MPA may be reduced as a result of competition between MPAG
and MPA for protein binding. Mean blood to plasma ratio of radioactivity
concentrations was approximately 0.6 indicating that MPA and MPAG do not
extensively distribute into the cellular fractions of blood.
In vitro studies to evaluate the effect of other agents on the binding
of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate
(at 25 mg/dL with HSA) and MPAG (at >460 µg/mL with plasma proteins) increased
the free fraction of MPA. At concentrations that exceeded what is encountered
clinically, cyclosporine, digoxin, naproxen, prednisone, propranolol,
tacrolimus, theophylline, tolbutamide, and warfarin did not increase the
free fraction of MPA. MPA at concentrations as high as 100 µg/mL had little
effect on the binding of warfarin, digoxin or propranolol, but decreased
the binding of theophylline from 53% to 45% and phenytoin from 90% to
87%.
Metabolism: Following oral and intravenous dosing, mycophenolate
mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism
to MPA occurs presystemically after oral dosing. MPA is metabolized principally
by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG)
which is not pharmacologically active. In vivo, MPAG is converted to MPA
via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino
moiety are also recovered in the urine following oral administration of
mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine,
N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.
Secondary peaks in the plasma MPA concentration-time profile are usually
observed 6 to 12 hours postdose. The coadministration of cholestyramine
(4 g tid) resulted in approximately a 40% decrease in the MPA AUC (largely
as a consequence of lower concentrations in the terminal portion of the
profile). These observations suggest that enterohepatic recirculation
contributes to MPA plasma concentrations.
Increased plasma concentrations of mycophenolate mofetil metabolites
(MIPA 50% increase and MPAG about 3-fold to 6-fold increase) are observed
in patients with renal insufficiency (see Special
Populations).
Excretion: Negligible amount of drug is excreted as MPA
(<1% of dose) in the urine. Orally administered radiolabeled mycophenolate
mofetil resulted in complete recovery of the administered dose, with 93%
of the administered dose recovered in the urine and 6% recovered in feces.
Most (about 87%) of the administered dose is excreted in the urine as
MPAG. At clinically encountered concentrations, MPA and MPAG are usually
not removed by hemodialysis. However, at high MPAG plasma concentrations
(>100 µg/mL), small amounts of MPAG are removed. Bile acid sequestrants,
such as cholestyramine, reduce MPA AUC by interfering with enterohepatic
circulation of the drug (see OVERDOSAGE).
Mean (± SD) apparent half-life and plasma clearance of MPA are 17.9 (+
6.5) hours and 193 (+ 48) mL/min following oral administration and 16.6
(+ 5.8) hours and 177 (+ 31) mL/min following IV administration, respectively.
Pharmacokinetics in Healthy Volunteers, Renal, and Cardiac Transplant
Patients: Shown below are the mean (± SD) pharmacokinetic parameters
for MPA following the administration of oral mycophenolate mofetil given
as single doses to healthy volunteers and multiple doses to renal and
cardiac transplant patients. After oral dosing the Cmax and
AUC of MPA in early transplant patients (<40 days posttransplant) are
approximately 45% to 50% and 20% to 30% lower, respectively, as compared
to healthy volunteers or to stable renal and cardiac transplant patients.
Mean MPA AUC values following administration of 1 g bid intravenous mycophenolate
mofetil over 2 hours to patients for 5 days were about 24% higher than
those observed after oral administration of a similar dose in the immediate
posttransplant phase.
|
Pharmacokinetic Parameters for MPA [mean (± SD)]
Following Administration of Mycophenolate Mofetil to Healthy Volunteers
(Single Dose),
Renal and Cardiac Transplant Patients (Multiple Doses)
|
| |
Dose/Route |
T max
(h) |
C max
(µg/ mL) |
Total AUC
(µg· h/ mL) |
Healthy Volunteers
(Single Dose) |
1 g/oral |
0.80
(± 0.36)
(n= 129) |
24.5
(± 9.5)
(n= 129) |
63.9
(± 16.2)
(n= 117) |
Renal Transplant
Patients (bid dosing)
Time After
Transplantation |
Dose/Route |
T max
(h) |
C max
(µg/ mL) |
Interdosing
Interval AUC 0-12
(µg· h/ mL) |
| 5 days |
1 g/iv |
1.58
(± 0.46)
(n= 31) |
12.0
(± 3.82)
(n= 31) |
40.8
(± 11.4)
(n= 31) |
| 6 days |
1 g/oral |
1.33
(± 1.05)
(n= 31) |
10.7
(± 4.83)
(n= 31) |
32.9
(± 15.0)
(n= 31) |
| Early (< 40 days) |
1 g/oral |
1.31
(± 0.76)
(n= 25) |
8.16
(± 4.50)
(n= 25) |
27.3
(± 10.9)
(n= 25) |
| Early (< 40 days) |
1.5 g/oral |
1.21
(± 0.81)
(n= 27) |
13.5
(± 8.18)
(n= 27) |
38.4
(± 15.4)
(n= 27) |
| Late (> 3 months) |
1.5 g/oral |
0.90
(± 0.24)
(n= 23) |
24.1
(± 12.1)
(n= 23) |
65.3
(± 35.4)
(n= 23) |
Cardiac Transplant
Patients (bid dosing)
Time After
Transplantation |
Dose/Route |
T max
(h) |
C max
(µg/ mL) |
Interdosing
Interval AUC0-12
(µg·h/ mL) |
| Early (Day before discharge) |
1.5 g/oral |
1.8
(± 1.3)
(n= 11) |
11.5
(± 6.8)
(n= 11) |
43.3
(± 20.8)
(n= 9) |
| Late (> 6 months) |
1.5 g/oral |
1.1
(± 0.7)
(n= 52) |
20.0
(± 9.4)
(n= 52) |
54.1 *
(± 20.4)
(n= 49) |
| * AUC0-12 values
quoted are extrapolated from data from samples collected over 4 hours. |
Two 500 mg tablets have been shown to be bioequivalent to four 250 mg
capsules.
Five mL of the 200 mg/mL constituted suspension have been shown to be
bioequivalent to four 250 mg capsules.
Special Populations
Shown below are the mean (± SD) pharmacokinetic parameters for MPA following
the administration of oral mycophenolate mofetil given as single doses
to nontransplant subjects with renal or hepatic impairment.
Pharmacokinetic Parameters
for MPA [mean (± SD)]
Following Single Doses of Mycophenolate Mofetil Capsules
in Chronic Renal and Hepatic Impairment |
Renal Impairment
(no. of patients) |
Dose |
Tmax
(h) |
Cmax
(µg/mL) |
AUC 0- 96
(µg· h/mL) |
Healthy Volunteers
GFR >80 mL/min/1.73m2
(n= 6) |
1 g |
0.75
(± 0.27) |
25.3
(± 7.99) |
45.0
(± 22.6) |
Mild Renal Impairment
GFR 50 to 80 mL/min/1.73m2
(n= 6) |
1 g |
0.75
(± 0.27) |
26.0
(± 3.82) |
59.9
(± 12.9) |
Moderate Renal Impairment
GFR 25 to 49 mL/min/1.73m2
(n= 6) |
1 g |
0.75
(± 0.27) |
19.0
(± 13.2) |
52.9
(± 25.5) |
Severe Renal Impairment
GFR <25 mL/min/1.73m2
(n= 7) |
1 g |
1.00
(± 0.41) |
16.3
(± 10.8) |
78.6
(± 46.4) |
Hepatic Impairment
(no. of patients) |
Dose |
Tmax
(h) |
Cmax
(µg/m L) |
AUC 0-48
(µg·h/mL) |
Healthy Volunteers
(n= 6) |
1 g |
0.63
(± 0.14) |
24.3
(± 5.73) |
29.0
(± 5.78) |
Alcoholic cirrhosis
(n= 18) |
1 g |
0.85
(± 0.58) |
22.4
(± 10.1) |
29.8
(± 10.7) |
Renal Insufficiency: In a single-dose study, MMF was administered
as capsule or intravenous infusion over 40 minutes. Plasma MPA AUC observed
after oral dosing to volunteers with severe chronic renal impairment [glomerular
filtration rate (GFR) <25 mL/min/1.73m²] was about 75% higher relative
to that observed in healthy volunteers (GFR >80 mL/min/1.73m²). In
addition, the single-dose plasma MPAG AUC was three-to six-fold higher
in volunteers with severe renal impairment than in volunteers with mild
renal impairment or healthy volunteers, consistent with the known renal
elimination of MPAG. No data are available on the safety of long-term
exposure to this level of MPAG.
Plasma MPA AUC observed after single dose (1 g) intravenous dosing to
volunteers (n= 4) with severe chronic renal impairment [glomerular filtration
rate (GFR) <25 mL/min/1.73m²] was 62.4 µg·h/mL (± 19.3). Multiple
dosing of mycophenolate mofetil in patients with severe chronic renal
impairment has not been studied (see PRECAUTIONS:
General and DOSAGE AND ADMINISTRATION).
In patients with delayed renal graft function posttransplant, mean MPA
AUC0-12 was comparable to that seen in
posttransplant patients without delayed graft function. Mean plasma MPAG
AUC0-12 was 2-to 3-fold higher than in
posttransplant patients without delayed graft function (see PRECAUTIONS:
General and DOSAGE AND ADMINISTRATION).
In 8 patients with primary non-function of the organ following renal
transplantation, plasma concentrations of MPAG accumulated about 6-to
8-fold after multiple dosing for 28 days. Accumulation of MPA was about
1-to 2-fold.
The pharmacokinetics of mycophenolate mofetil are not altered by hemodialysis.
Hemodialysis usually does not remove MPA or MPAG. At high concentrations
of MPAG (> 100 µg/mL), hemodialysis removes only small amounts of MPAG.
Hepatic Insufficiency: In a single-dose (1 g, oral) study
of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic
MPA glucuronidation processes appeared to be relatively unaffected by
hepatic parenchymal disease when pharmacokinetic parameters of healthy
volunteers and alcoholic cirrhosis patients within this study were compared.
However, it should be noted that for unexplained reasons, the healthy
volunteers in this study had about a 50% lower AUC as compared to healthy
volunteers in other studies, thus making comparisons between volunteers
with alcoholic cirrhosis and healthy volunteers difficult. Effects of
hepatic disease on this process probably depend on the particular disease.
Hepatic disease with other etiologies may show a different effect. In
a single-dose (1 g) intravenous study of 6 volunteers with alcoholic cirrhosis,
MPA AUC was 44.1 µg·h/mL (± 15.5).
Pediatrics: Very limited pharmacokinetic data are available
for pediatric renal transplant recipients. Data on these patients are
presented in the table below:
Pharmacokinetic Parameters
for MPA [mean ± (SD)]
Following Multiple Oral Doses of Mycophenolate Mofetil in Pediatric
Renal
Transplant Patients 21 Days Posttransplant |
| Age Range |
Dose |
Tmax
(h) |
Cmax
(µg/mL) |
AUC 0-12
(µg·h/mL) |
³3 mo to <6 yr
(Mean = 2.75)
(n= 4) |
15 mg/kg bid |
1.25
(± 0.87) |
3.70
(± 2.08) |
13.6
(± 8.69) |
³6 yr to <12 yr
(Mean = 9.0)
(n= 4) |
15 mg/kg bid |
0.50
(± 0.00) |
13.5
(± 4.48) |
23.4
(± 2.84) |
³12 yr to 18 yr
(Mean = 15.6)
(n= 5) |
15 mg/kg bid |
0.50
(± 0.00) |
13.2
(± 6.86) |
30.0
(± 8.34) |
³6 yr to <12 yr
(Mean = 9.8)
(n= 5) |
23 mg/kg bid |
1.46
(± 0.79) |
17.0
(± 20.0) |
40.1
(± 17.6) |
³12 yr to 18 yr
(Mean = 14.6)
(n= 6) |
23 mg/kg bid |
1.32
(± 0.76) |
11.5
(± 10.2) |
31.1
(± 11.4) |
Gender: Data obtained from several studies were pooled
to look at any gender-related differences in the pharmacokinetics of MPA
(data were adjusted to 1 g oral dose). Mean (± SD) MPA AUC0-12
for males (n= 79) was 32.0 (± 14.5) and for females (n= 41) was 36.5 (±
18.8) µg·h/mL while mean (± SD) MPA Cmax was 9.96 (± 6.19)
in the males and 10.6 (± 5.64) µg/mL in the females. These differences
are not of clinical significance.
Geriatric Use: Pharmacokinetics in the elderly have not
been studied.
CLINICAL STUDIES
The safety and efficacy of CellCept in combination with corticosteroids
and cyclosporine for the prevention of organ rejection were assessed in
renal transplant patients in three randomized, double-blind, multicenter
trials and in cardiac patients in one randomized double-blind, multicenter
trial.
Renal Transplant
These three studies compared two dose levels of oral CellCept (1 g bid
and 1.5 g bid) with azathioprine (2 studies) or placebo (1 study) when
administered in combination with cyclosporine (Sandimmune®) and corticosteroids
to prevent acute rejection episodes. One study also included antithymocyte
globulin (ATGAM®) induction therapy. These studies are described by geographic
location of the investigational sites. One study was conducted in the
USA at 14 sites, one study was conducted in Europe at 20 sites, and one
study was conducted in Europe, Canada, and Australia at a total of 21
sites.
The primary efficacy endpoint was the proportion of patients in each
treatment group who experienced treatment failure within the first 6 months
after transplantation (defined as biopsyproven acute rejection on treatment
or the occurrence of death, graft loss or early termination from the study
for any reason without prior biopsy-proven rejection). CellCept, when
administered with antithymocyte globulin (ATGAM®) induction (one study)
and with cyclosporine and corticosteroids (all three studies), was compared
to the following three therapeutic regimens: (1) antithymocyte globulin
(ATGAM®) induction/azathioprine/cyclosporine/corticosteroids, (2) azathioprine/cyclosporine/corticosteroids,
and (3) cyclosporine/corticosteroids.
CellCept, in combination with corticosteroids and cyclosporine reduced
(statistically significant at the <0.05 level) the incidence of treatment
failure within the first 6 months following transplantation. The following
tables summarize the results of these studies. These tables show (1) the
proportion of patients experiencing treatment failure, (2) the proportion
of patients who experienced biopsy-proven acute rejection on treatment,
and (3) early termination, for any reason other than graft loss or death,
without a prior biopsy-proven acute rejection episode. Patients who prematurely
discontinued treatment were followed for the occurrence of death or graft
loss, and the cumulative incidence of graft loss and patient death are
summarized separately. Patients who prematurely discontinued treatment
were not followed for the occurrence of acute rejection after termination.
More patients discontinued receiving CellCept (without prior biopsy-proven
rejection, death or graft loss) than discontinued in the control groups,
with the highest rate in the CellCept 3 g/day group. Therefore, the acute
rejection rates may be underestimates, particularly in the CellCept 3
g/day group.
Renal Transplant Studies
Incidence of Treatment Failure
(Biopsy-proven Rejection or Early Termination for Any Reason)
|
USA Study
(N= 499 patients) |
CellCept
2 g/day
(n= 167 patients) |
CellCept
3 g/day
(n= 166 patients) |
Azathioprine
1 to 2 mg/kg/day
(n= 166 patients) |
| All treatment failures |
31.1% |
31.3% |
47.6% |
Early termination
without prior acute
rejection * |
9.6% |
12.7% |
6.0% |
Biopsy- proven
rejection episode on
treatment |
19.8% |
17.5% |
38.0% |
Europe/ Canada/
Australia Study
(N= 503 patients) |
CellCept
2 g/day
(n= 173 patients) |
CellCept
3 g/day
(n= 164 patients) |
Azathioprine
100 to 150 mg/day
(n= 166 patients) |
| All treatment failures |
38.2% |
34.8% |
50.0% |
Early termination
without prior acute
rejection* |
13.9% |
15.2% |
10.2% |
Biopsy- proven
rejection episode on
treatment |
19.7% |
15.9% |
35.5% |
Europe Study
(N= 491 patients) |
CellCept
2 g/day
(n= 165 patients) |
CellCept
3 g/day
(n= 160 patients) |
Placebo
(n= 166 patients) |
| All treatment failures |
30.3% |
38.8% |
56.0% |
Early termination
without prior acute
rejection * |
11.5% |
22.5% |
7.2% |
Biopsy- proven
rejection episode on
treatment |
17.0% |
13.8% |
46.4% |
*Does not include death and graft loss as reason for early termination.
Cumulative incidence of 12-month graft loss and patient death are presented
below. No advantage of CellCept with respect to graft loss and patient
death was established. Numerically, patients receiving CellCept 2 g/day
and 3 g/day experienced a better outcome than controls in all three studies;
patients receiving CellCept 2 g/day experienced a better outcome than
CellCept 3 g/day in two of the three studies. Patients in all treatment
groups who terminated treatment early were found to have a poor outcome
with respect to graft loss and patient death at 1 year.
Renal Transplant Studies
Cumulative Incidence of Combined Graft Loss
and Patient Death at 12 Months |
| Study |
CellCept
2 g/ day |
CellCept
3 g/ day |
Control
(Azathioprine or
Placebo) |
| USA |
8.5% |
11.5% |
12.2% |
| Europe/ Canada/ Australia |
11.7% |
11.0% |
13.6% |
| Europe |
8.5% |
10.0% |
11.5% |
Cardiac Transplant
A double-blind, randomized, comparative, parallel-group, multicenter
study in primary cardiac transplant recipients was performed at 20 centers
in the United States, one in Canada, five in Europe and two in Australia.
The total number of patients enrolled was 650; 72 never received study
drug and 578 received study drug. Patients received CellCept 1.5 g bid
(n= 289) or azathioprine 1.5 to 3 mg/kg/day (n= 289), in combination with
cyclosporine (Sandimmune® or Neoral®) and corticosteroids as maintenance
immunosuppressive therapy. The two primary efficacy endpoints were: (1)
the proportion of patients who, after transplantation, had at least one
endomyocardial biopsy-proven rejection with hemodynamic compromise, or
were retransplanted or died, within the first 6 months, and (2) the proportion
of patients who died or were transplanted during the first 12 months following
transplantation. Patients who prematurely discontinued treatment were
followed for the occurrence of allograft rejection for up to 6 months
and for the occurrence of death for 1 year.
Rejection: No difference was established between CellCept
and azathioprine (AZA) with respect to biopsy-proven rejection with hemodynamic
compromise, as presented below.
| Rejection at 6 Months |
| |
All Patients |
Treated
Patients |
AZA
N = 323 |
CellCept
N = 327 |
AZA
N = 289 |
CellCept
N = 289 |
Biopsy-proven rejection with
hemodynamic compromise * |
121 (38%) |
120 (37%) |
100 (35%) |
92 (32%) |
*Hemodynamic compromise occurred if any of the following criteria were
met: pulmonary capillary wedge pressure ³20
mm or a 25% increase; cardiac index <2.01/min/m² or a 25% decrease;
ejection fraction £30%; pulmonary artery
oxygen saturation £60% or a 25% decrease;
presence of new S3 gallop; fractional shortening was £20%
or a 25% decrease; inotropic support required to manage the clinical condition.
Survival: CellCept was shown to be at least as effective
as AZA in preventing death or retransplantation at 1 year, as presented
below.
| Death or Retransplantation at 1
Year |
| |
All Patients |
Treated
Patients |
AZA
N = 323 |
CellCept
N = 327 |
AZA
N = 289 |
CellCept
N = 289 |
Death or
Retransplantation |
49 (15.2%) |
42 (12.8%) |
33 (11.4%) |
18 (6.2%) |
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