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
Rapamune Pharmacology, Pharmacokinetics, Studies, Metabolism - Sirolimus
Rapamune Pharmacology, Pharmacokinetics, Studies, Metabolism - Sirolimus
CLINICAL PHARMACOLOGY
Mechanism of Action
Sirolimus inhibits T lymphocyte activation and proliferation that occurs
in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15)
stimulation by a mechanism that is distinct from that of other immunosuppressants.
Sirolimus also inhibits antibody production. In cells, sirolimus binds
to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive
complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity.
This complex binds to and inhibits the activation of the mammalian Target
Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses
cytokine-driven T-cell proliferation, inhibiting the progression from
the G 1 to the S phase of the cell cycle.
Studies in experimental models show that sirolimus prolongs allograft
(kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone
marrow) surivival in mice, rats, pigs, and/or primates. Sirolimus reverses
acute rejection of heart and kidney allografts in rats and prolonged the
graft survival in presensitized rats. In some studies, the immunosuppressive
effect of sirolimus lasted up to 6 months after discontinuation of therapy.
This tolerization effect is alloantigen specific.
In rodent models of autoimmune disease, sirolimus suppresses immune-mediated
events associated with systemic lupus erythematosus, collagen-induced
arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental
allergic encephalomyelitis, graft-versus-host disease, and autoimmune
uveoretinitis.
Pharmacokinetics
Sirolimus pharmacokinetic activity has been determined following oral
administration in healthy subjects, pediatric dialysis patients, hepatically-impaired
patients, and renal transplant patients.
Absorption
Following administration of Rapamune® Oral Solution, sirolimus is rapidly
absorbed, with a mean time-to-peak concentration (t max ) of
approximately 1 hour after a single dose in healthy subjects and approximately
2 hours after multiple oral doses in renal transplant recipients. The
systemic availability of sirolimus was estimated to be approximately 14%
after the administration of Rapamune Oral Solution. The mean bioavailability
of sirolimus after administration of the tablet is about 27% higher relative
to the oral solution. Sirolimus oral tablets are not bioequivalent to
the oral solution; however, clinical equivalence has been demonstrated
at the 2-mg dose level. (See CLINICAL STUDIES and DOSAGE
AND ADMINISTRATION ). Sirolimus concentrations, following the
administration of Rapamune Oral Solution to stable renal transplant patients,
are dose proportional between 3 and 12 mg/m 2 .
Food effects: In 22 healthy volunteers receiving
Rapamune Oral Solution, a high-fat meal (1.88 kcal, 54.7% fat) altered
the bioavailability characteristics of sirolimus. Compared to fasting,
a 34% decrease in the peak blood sirolimus concentration (C max ),
a 3.5-fold increase in the time-to-peak concentration (t max ),
and a 35% increase in total exposure (AUC) was observed. After administration
of Rapamune Tablets and a high-fat meal in 24 healthy volunteers, C max
, t max , and AUC showed increases of 65%, 32%, and 23%,
respectively. To minimize variability, both Rapamune Oral Solution and
Tablets should be taken consistently with or without food (See DOSAGE
AND ADMINISTRATION ).
Distribution
The mean (±SD) blood-to-plasma ratio of sirolimus was 36 (± 17.9) in
stable renal allograft recipients, indicating that sirolimus is extensively
partitioned into formed blood elements. The mean volume of distribution
(V ss /F) of sirolimus is 12 ± 7.52 L/kg. Sirolimus is extensively
bound (approximately 92%) to human plasma proteins. In man, the binding
of sirolimus was shown mainly to be associated with serum albumin (97%),
(alpha) 1 -acid glycoprotein, and lipoproteins.
Metabolism
Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and
P-glycoprotein. Sirolimus is extensively metabolized by O-demethylation
and/or hydroxylation. Seven (7) major metabolites, including hydroxy,
demethyl, and hydroxydemethyl, are identifiable in whole blood. Some of
these metabolites are also detectable in plasma, fecal, and urine samples.
Glucuronide and sulfate conjugates are not present in any of the biologic
matrices. Sirolimus is the major component in human whole blood and contributes
to more than 90% of the immunosuppressive activity.
Excretion
After a single dose of [ 14 C]sirolimus in healthy volunteers,
the majority (91%) of radioactivity was recovered from the feces, and
only a minor amount (2.2%) was excreted in urine.
Pharmacokinetics in renal transplant patients
Rapamune Oral Solution: Pharmacokinetic parameters for sirolimus
oral solution given daily in combination with cyclosporine and corticosteroids
in renal transplant patients are summarized below based on data collected
at months 1, 3, and 6 after transplantation. There were no significant
differences in any of these parameters with respect to treatment group
or month.
SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD)
IN RENAL
TRANSPLANT PATIENTS (MULTIPLE DOSE ORAL SOLUTION) a ,
b
| n |
Dose |
C max,ss c
(ng/mL) |
t max,ss
(h) |
AUC t,ss c
(ng·h/mL) |
CL/F/WT d
(mL/h/kg) |
| 19 |
2 mg |
12.2 ± 6.2 |
3.01 ± 2.40 |
158 ± 70 |
182 ± 72 |
| 23 |
5 mg |
37.4 ± 21 |
1.84 ± 1.30 |
396 ± 193 |
221 ± 143 |
| a: Sirolimus administered four hours after cyclosporine
oral solution (MODIFIED) (e.g., Neoral® Oral Solution) and/or cyclosporine
capsules (MODIFIED) (e.g., Neoral® Soft Gelatin Capsules). |
| b: As measured by the Liquid Chromatographic/Tandem Mass
Spectrometric Method (LC/MS/MS). |
| c: These parameters were dose normalized prior to the
statistical comparison. |
| d: CL/F/WT = oral dose clearance. |
Whole blood sirolimus trough concentrations, as measured by immunoassay,
(mean ± SD) for the 2 mg/day and 5 mg/day dose groups were 8.59 ± 4.01
ng/mL (n = 226) and 17.3 ± 7.4 ng/mL (n = 219), respectively. Whole blood
trough sirolimus concentrations, as measured by LC/MS/MS, were significantly
correlated (r 2 = 0.96) with AUC [tgr ],ss . Upon
repeated twice daily administration without an initial loading dose in
a multiple-dose study, the average trough concentration of sirolimus increases
approximately 2 to 3-fold over the initial 6 days of therapy at which
time steady state is reached. A loading dose of 3 times the maintenance
dose will provide near steady-state concentrations within 1 day in most
patients. The mean ± SD terminal elimination half life (t 1/2 )
of sirolimus after multiple dosing in stable renal transplant patients
was estimated to be about 62 ± 16 hours.
Rapamune Tablets: Pharmacokinetic parameters for sirolimus
tablets administered daily in combination with cyclosporine and corticosteroids
in renal transplant patients are summarized below based on data collected
at months 1 and 3 after transplantation.
SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD)
IN RENAL
TRANSPLANT PATIENTS (MULTIPLE DOSE TABLETS) a , b
| n |
Dose
(2 mg/day) |
C max,ss c
(ng/mL) |
t max,ss
(h) |
AUC t,ss c
(ng·h/mL) |
CL/F/WT d
(mL/h/kg) |
| 17 |
Oral solution |
14.4 ± 5.3 |
2.12 ± 0.84 |
194 ± 78 |
173 ± 50 |
| 13 |
Tablets |
15.0 ± 4.9 |
3.46 ± 2.40 |
230 ± 67 |
139 ± 63 |
| a: Sirolimus administered four hours after cyclosporine
oral solution (MODIFIED) (e.g., Neoral® Oral Solution) and/or cyclosporine
capsules (MODIFIED) (e.g., Neoral® Soft Gelatin Capsules). |
| b: As measured by the Liquid Chromatographic/Tandem
Mass Spectrometric Method (LC/MS/MS). |
| c: These parameters were dose normalized prior to the
statistical comparison. |
| d: CL/F/WT = oral dose clearance. |
Whole blood sirolimus trough concentrations (mean ± SD), as measured
by immunoassay, for the 2 mg oral solution and 2 mg tablets over 6 months,
were 8.94 ± 4.36 ng/mL (n = 172) and 9.48 ± 3.85 ng/mL (n = 179), respectively.
Whole blood trough sirolimus concentrations, as measured by LC/MS/MS,
were significantly correlated (r 2 = 0.85) with AUC [tgr
],ss . Mean whole blood sirolimus trough concentrations in patients
receiving either Rapamune Oral Solution or Rapamune Tablets with a loading
dose of three times the maintenance dose achieved steady-state concentrations
within 24 hours after the start of dose administration.
Special Populations
Hepatic impairment: Sirolimus (15 mg) was administered
as a single oral dose to 18 subjects with normal hepatic function and
to 18 patients with Child-Pugh classification A or B hepatic impairment,
in which hepatic impairment was primary and not related to an underlying
systemic disease. Shown below are the mean ± SD pharmacokinetic parameters
following the administration of sirolimus oral solution.
SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD)
IN
18 HEALTHY SUBJECTS AND 18 PATIENTS WITH
HEPATIC IMPAIRMENT (15 MG SINGLE DOSE - ORAL SOLUTION)
| Population |
C max,ss a
(ng/mL) |
t max
(h) |
AUC 0-(infinity)
(ng·h/mL) |
CL/F/WT
(mL/h/kg) |
|
Healthy subjects
|
78.2 ± 18.3 |
0.82 ± 0.17 |
970 ± 272 |
215 ± 76 |
|
Hepatic impairment
|
77.9 ± 23.1 |
0.84 ± 0.17 |
1567 ± 616 |
144 ± 62 |
| a: As measured by (LC/MS/MS) |
Compared with the values in the normal hepatic group, the hepatic impairment
group had higher mean values for sirolimus AUC (61%) and t 1/2 (43%)
and had lower mean values for sirolimus CL/F/WT (33%). The mean t 1/2
increased from 79 ± 12 hours in subjects with normal hepatic function
to 113 ± 41 hours in patients with impaired hepatic function. The rate
of absorption of sirolimus was not altered by hepatic disease, as evidenced
by C max and t max values. However, hepatic diseases
with varying etiologies may show different effects and the pharmacokinetics
of sirolimus in patients with severe hepatic dysfunction is unknown. Dosage
adjustment is recommended for patients with mild to moderate hepatic impairment
(see DOSAGE AND ADMINISTRATION ).
Renal impairment: The effect of renal impairment
on the pharmacokinetics of sirolimus is not known. However, there is minimal
(2.2%) renal excretion of the drug or its metabolites.
Pediatric Limited pharmacokinetic data are
available in pediatric patients. The table below summarizes pharmacokinetic
data obtained in pediatric dialysis patients with chronically impaired
renal function.
SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD)
IN PEDIATRIC PATIENTS WITH STABLE CHRONIC RENAL FAILURE MAINTAINED ON
HEMODIALYSIS OR PERITONEAL DIALYSIS
(1, 3, 9, 15 MG/M 2 SINGLE DOSE)
| Age Group (y) |
n |
t max (h) |
t 1/2 (h) |
CL/F/WT (mL/h/kg) |
| 5-11 |
9 |
1.1 ± 0.5 |
71 ± 40 |
580 ± 450 |
| 12-18 |
11 |
0.79 ± 0.17 |
55 ± 18 |
450 ± 232 |
Geriatric: Clinical studies of Rapamune did
not include a sufficient number of patients > 65 years of age to determine
whether they will respond differently than younger patients. After the
administration of Rapamune Oral Solution, sirolimus trough concentration
data in 35 renal transplant patients > 65 years of age were similar
to those in the adult population (n = 822) 18 to 65 years of age. Similar
results were obtained after the administration of Rapamune Tablets to
12 renal transplant patients > 65 years of age compared with adults
(n = 167) 18 to 65 years of age.
Gender: After the administration of Rapamune
Oral Solution, sirolimus oral dose clearance in males was 12% lower than
that in females; male subjects had a significantly longer t 1/2 than
did female subjects (72.3 hours versus 61.3 hours). A similar trend in
the effect of gender on sirolimus oral dose clearance and t 1/2 was
observed after the administration of Rapamune Tablets. Dose adjustments
based on gender are not recommended.
Race: In large phase III trials using Rapamune
Oral Solution and cyclosporine oral solution (MODIFIED) (e.g., Neoral®
Oral Solution) and/or cyclosporine capsules (MODIFIED) (e.g., Neoral®
Soft Gelatin Capsules), there were no significant differences in mean
trough sirolimus concentrations over time between black (n = 139) and
non-black (n = 724) patients during the first 6 months after transplantation
at sirolimus doses of 2 mg/day and 5 mg/day. Similarly, after administration
of Rapamune Tablets (2 mg/day) in a phase III trial, mean sirolimus trough
concentrations over 6 months were not significantly different among black
(n = 51) and non-black (n = 128) patients.
CLINICAL STUDIES
Rapamune® Oral Solution: The safety and efficacy of Rapamune®
Oral Solution for the prevention of organ rejection following renal transplantation
were assessed in two randomized, double-blind, multicenter, controlled
trials. These studies compared two dose levels of Rapamune Oral Solution
(2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study
2) when administered in combination with cyclosporine and corticosteroids.
Study 1 was conducted in the United States at 38 sites. Seven hundred
nineteen (719) patients were enrolled in this trial and randomized following
transplantation; 284 were randomized to receive Rapamune Oral Solution
2 mg/day, 274 were randomized to receive Rapamune Oral Solution 5 mg/day,
and 161 to receive azathioprine 2-3 mg/kg/day. Study 2 was conducted in
Australia, Canada, Europe, and the United States, at a total of 34 sites.
Five hundred seventy-six (576) patients were enrolled in this trial and
randomized before transplantation; 227 were randomized to receive Rapamune
Oral Solution 2 mg/day, 219 were randomized to receive Rapamune Oral Solution
5 mg/day, and 130 to receive placebo. In both studies, the use of antilymphocyte
antibody induction therapy was prohibited. In both studies, the primary
efficacy endpoint was the rate of efficacy failure in the first 6 months
after transplantation. Efficacy failure was defined as the first occurrence
of an acute rejection episode (confirmed by biopsy), graft loss, or death.
The tables below summarize the results of the primary efficacy analyses
from these trials. Rapamune Oral Solution, at doses of 2 mg/day and 5
mg/day, significantly reduced the incidence of efficacy failure (statistically
significant at the <0.025 level; nominal significance level adjusted
for multiple [2] dose comparisons) at 6 months following transplantation
compared to both azathioprine and placebo.
INCIDENCE (%) OF THE PRIMARY ENDPOINT AT 6 MONTHS:
STUDY 1 a
|
Parameter
|
Rapamune®
Oral Solution
2 mg/day
(n = 284)
|
Rapamune®
Oral Solution
5 mg/day
(n = 274) |
Azathioprine
2-3 mg/kg/day
(n = 161) |
|
Efficacy failure at 6 months
|
18.7 |
16.8 |
32.3 |
|
Components of efficacy failure
|
|
Biopsy-proven acute rejection
|
16.5 |
11.3 |
29.2 |
|
Graft loss
|
1.1 |
2.9 |
2.5 |
|
Death
|
0.7 |
1.8 |
0 |
|
Lost to follow-up
|
0.4 |
0.7 |
0.6 |
| a: Patients received cyclosporine and corticosteroids.
|
INCIDENCE (%) OF THE PRIMARY ENDPOINT AT 6 MONTHS:
STUDY 2 a
|
Parameter
|
Rapamune®
Oral Solution
2 mg/day
(n = 227) |
Rapamune®
Oral Solution
5 mg/day
(n = 219) |
Placebo
(n = 130) |
|
Efficacy failure at 6 months
|
30.0 |
25.6 |
47.7 |
|
Components of efficacy failure
|
|
Biopsy-proven acute rejection
|
24.7 |
19.2 |
41.5 |
|
Graft loss
|
3.1 |
3.7 |
3.9 |
|
Death
|
2.2 |
2.7 |
2.3 |
|
Lost to follow-up
|
0 |
0 |
0 |
| a: Patients received cyclosporine and corticosteroids.
|
Patient and graft survival at 1 year were co-primary endpoints. The table
below shows graft and patient survival at 1 year in Study 1 and Study
2. The graft and patient survival rates at 1 year were similar in the
Rapamune- and comparator-treated patients.
1 YEAR GRAFT AND PATIENT SURVIVAL (%) a
|
Parameter
|
Rapamune®
Oral Solution
2 mg/day |
Rapamune®
Oral Solution
5 mg/day |
Azathioprine
2-3 mg/kg/day |
Placebo |
|
Study 1
|
(n = 284) |
(n = 274) |
(n = 161) |
|
|
Graft survival
|
94.7 |
92.7 |
93.8 |
|
|
Patient survival
|
97.2 |
96.0 |
98.1 |
|
|
Study 2
|
(n = 227) |
(n = 219) |
|
(n = 130) |
|
Graft survival
|
89.9 |
90.9 |
|
87.7 |
|
Patient survival
|
96.5 |
95.0 |
|
94.6 |
| a: Patients received cyclosporine and corticosteroids.
|
The reduction in the incidence of first biopsy-confirmed acute rejection
episodes in Rapamune-treated patients compared to the control groups included
a reduction in all grades of rejection.
PERCENTAGE OF EFFICACY FAILURE BY RACE AT 6 MONTHS
|
Parameter
|
Rapamune®
Oral Solution
2 mg/day |
Rapamune®
Oral Solution
5 mg/day |
Azathioprine
2-3 mg/kg/day |
Placebo |
|
Study 1
|
|
Black (n=166)
|
34.9 (n=63) |
18.0 (n=61) |
33.3 (n=42) |
|
|
Non-black (n=553)
|
14.0 (n=221) |
16.4 (n=213) |
31.9 (n=119) |
|
|
Study 2
|
|
Black (n=66)
|
30.8 (n=26) |
33.7 (n=27) |
|
38.5 (n=13) |
|
Non-black (n=510)
|
29.9 (n=201) |
24.5 (n=192) |
|
48.7 (n=117) |
In Study 1, which was prospectively stratified by race within center,
efficacy failure was similar for Rapamune Oral Solution 2 mg/day and lower
for Rapamune Oral Solution 5 mg/day compared to azathioprine in black
patients. In Study 2, which was not prospectively stratified by race,
efficacy failure was similar for both Rapamune Oral Solution doses compared
to placebo in black patients. The decision to use the higher dose of Rapamune
Oral Solution in black patients must be weighed against the increased
risk of dose-dependent adverse events that were observed with the Rapamune
Oral Solution 5 mg dose (see ADVERSE
REACTIONS).
OVERALL CALCULATED GLOMERULAR FILTRATION RATES
(CC/MIN)
BY NANKIVELL EQUATION AT 12 MONTHS POST TRANSPLANT
|
Parameter
|
Rapamune®
Oral Solution
2 mg/day |
Rapamune®
Oral Solution
5 mg/day |
Azathioprine
2-3 mg/kg/day |
Placebo |
|
Study 1
|
(n=233) |
(n=226) |
(n=127) |
|
|
Mean (SE)
|
57.4 (1.28) |
55.1 (1.28) |
65.9 (1.69) |
|
|
Study 2
|
(n=190) |
(n=175) |
|
(n=101) |
|
Mean (SE)
|
54.9 (1.26) |
52.9 (1.46) |
|
61.7 (1.81) |
Mean glomerular filtration rates (GFR) at one year post transplant were
calculated by using the Nankivell equation for all subjects in Studies
1 and 2 who had serum creatinine measured at 12 months. In Studies 1 and
2 mean GFR, at 12 months, were lower in patients treated with cyclosporine
and Rapamune Oral Solution compared to those treated with cyclosporine
and the respective azathioprine or placebo control.
Within each treatment group in Studies 1 and 2, mean GFR at one year
post transplant was lower in patients who experienced at least 1 episode
of biopsy-proven acute rejection, compared to those who did not.
Renal function should be monitored and appropriate adjustment of the
immunosuppression regimen should be considered in patients with elevated
serum creatinine levels (see PRECAUTIONS
).
Rapamune® Tablets: The safety and efficacy of Rapamune Oral
Solution and Rapamune Tablets for the prevention of organ rejection following
renal transplantation were compared in a randomized multicenter controlled
trial (Study 3). This study compared a single dose level (2 mg, once daily)
of Rapamune Oral Solution and Rapamune Tablets when administered in combination
with cyclosporine and corticosteroids. The study was conducted at 30 centers
in Australia, Canada, and the United States. Four hundred seventy-seven
(477) patients were enrolled in this study and randomized before transplantation;
238 patients were randomized to receive Rapamune Oral Solution 2 mg/day
and 239 patients were randomized to receive Rapamune Tablets 2 mg/day.
In this study, the use of antilymphocyte antibody induction therapy was
prohibited. The primary efficacy endpoint was the rate of efficacy failure
in the first 3 months after transplantation. Efficacy failure was defined
as the first occurrence of an acute rejection episode (confirmed by biopsy),
graft loss, or death.
The table below summarizes the result of the primary efficacy analysis
at 3 months from this trial. The overall rate of efficacy failure in the
tablet treatment group was equivalent to the rate in the oral solution
treatment group.
INCIDENCE (%) OF THE PRIMARY ENDPOINT AT 3 MONTHS:
STUDY 3 a
| |
Rapamune®
Oral Solution
(n = 238) |
Rapamune®
Tablets
(n = 239) |
|
Efficacy Failure at 3 months
|
23.5 |
24.7 |
|
Components of efficacy failure
|
|
Biopsy-proven acute rejection
|
18.9 |
17.6 |
|
Graft loss
|
3.4 |
6.3 |
|
Death
|
1.3 |
0.8 |
| a: Patients received cyclosporine and corticosteroids.
|
The table below summarizes the results of the primary efficacy analysis
at 6 months after transplantation.
INCIDENCE (%) OF THE PRIMARY ENDPOINT AT 6 MONTHS:
STUDY 3 a
| |
Rapamune®
Oral Solution
(n = 238) |
Rapamune®
Tablets
(n = 239) |
|
Efficacy Failure at 6 months
|
26.1 |
27.2 |
|
Components of efficacy failure
|
|
Biopsy-proven acute rejection
|
21.0 |
19.2 |
|
Graft loss
|
3.4 |
6.3 |
|
Death
|
1.7 |
1.7 |
| a: Patients received cyclosporine and corticosteroids.
|
Graft and patient survival at 12 months were co-primary efficacy endpoints.
There was no significant difference between the oral solution and tablet
formulations for both graft and patient survival. Graft survival was 92.0%
and 88.7% for the oral solution and tablet treatment groups, respectively.
The patient survival rates in the oral solution and tablet treatment groups
were 95.8% and 96.2%, respectively.
The mean GFR at 12 months, calculated by the Nankivell equation, were
not significantly different for the oral solution group and for the tablet
group.
The table below summarizes the mean GFR at one-year post-transplantation
for all subjects in Study 3 who had serum creatinine measured at 12 months.
OVERALL CALCULATED GLOMERULAR FILTRATION RATES (CC/MIN) BY NANKIVELL
EQUATION AT 12 MONTHS POST TRANSPLANT: STUDY 3
| |
Rapamune®
Oral Solution |
Rapamune®
Tablets |
|
Mean (SE)
|
58.3 (1.64) |
58.5 (1.44) |
| n = 166 |
n = 162 |
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