Full text of DOI:10.2165/00003088-200140080-00002

Clin Pharmacokinet 2001; 40 (8): 573-585
0312-5963/01/0008-0573/$22.00/0
DRUG DISPOSITION
© Adis International Limited. All rights reserved.
Clinical Pharmacokinetics of Sirolimus
Kamran Mahalati and Barry D. Kahan
The University of Texas-Houston Medical School, Department of Surgery,
Division of Immunology and Organ Transplantation, Houston, Texas, USA
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
1. Chemical Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
2. Analytical Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
2.1 High Performance Liquid Chromatography with Detection by
Tandem Mass Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
2.2 Liquid Chromatography with Ultraviolet Detection . . . . . . . . . . . . . . . . . . . . . . . . 575
2.3 Radioreceptor Assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576
2.4 Microparticle Enzyme Immunoassay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576
3. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
3.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
3.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578
3.3 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
3.4 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
4. Therapeutic Drug Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
Sirolimus (previously known as rapamycin), a macrocyclic lactone, is a potent
immunosuppressive agent. Sirolimus was recently approved by the US Food and
Drug Administration, on the basis of 2 large, double-blind, prospective clinical
trials, for use in kidney transplant recipients at a fixed dosage of 2 or 5 mg/day
in addition to full dosages of cyclosporin and prednisone. However, despite the
fixed dosage regimens used in these pivotal trials, pharmacokinetic and clinical
data show that sirolimus is a critical-dose drug requiring therapeutic drug moni-
toring to minimise drug-related toxicities and maximise efficacy.
Abstract
Assays using high performance liquid chromatography coupled to mass spec-
trometry, although cumbersome, are the gold standard for evaluating other com-
monly used assays, such as liquid chromatography with ultraviolet detection,
radioreceptor assay and microparticle enzyme immunoassay.
Sirolimus is available in oral solution and tablet form. It has poor oral absorp-
tion and distributes widely in tissues, displaying not only a wide inter- and intra-
patient variability in drug clearance, but also less than optimal correlations
between whole blood concentrations and drug dose, demographic features or
patient characteristics. Furthermore, the critical role of the cytochrome P450 3A4
system for sirolimus biotransformation leads to extensive drug-drug interactions,
among which are increases in cyclosporin concentrations. Thus, sirolimus is now
being used to reduce or eliminate exposure to cyclosporin or corticosteroids. The
long elimination half-life of sirolimus necessitates a loading dose but allows once

574
Mahalati & Kahan
daily administration, which is more convenient and thereby could help to improve
patient compliance.
This review emphasises the importance of blood concentration monitoring in
optimising the use of sirolimus. The excellent correlation between steady-state
trough concentration (at least 4 days after inception of, or change in, therapy) and
area under the concentration-time curve makes the former a simple and reliable
index for monitoring sirolimus exposure. Target trough concentration ranges de-
pend on the concomitant immunosuppressive regimen, but a range of 5 to 15 μg/L
is appropriate if cyclosporin is being used at trough concentrations of 75 to 150
μg/L. Weekly monitoring is recommended for the first month and bi-weekly for
the next month; thereafter, concentration measurements are necessary only if
warranted clinically.
Sirolimus (Wyeth-Ayerst, Princeton, NJ, USA),
uble in water. The ultraviolet absorption spectrum
shows a major peak at 277nm and minor peaks at
267 and 288nm.[1] The compound is sensitive to
light and temperature, and blood samples, partic-
ularly after extraction, must be shielded to prevent
degradation. However, a recent report suggests that
the drug in the blood resists the degradative effects
of freeze-thaw cycles.[7]
formerly known as rapamycin, is a macrocyclic
lactone (fig. 1). Sirolimus is a fermentation product
of Streptomyces hygroscopicus, which was discov-
ered in the soil of Rapa Nui (Easter Island).[1] Al-
though first developed as an antifungal agent, the
drug was later found to have potent antiprolifera-
tive and immunosuppressive properties.[2,3]
Sirolimus displays a synergistic action with, and
a distinctive mechanism of action from, that of
calcineurin inhibitors.[4,5] It inhibits both generation
of the costimulatory signal during G0 to G1 activation
of lymphocytes, and the post-transduction events
after cytokine stimulation during G1.[6]
Previous reviews have primarily concentrated
on the pharmacokinetics of sirolimus rather than on
therapeutic monitoring, mainly because the clinical
data on the correlations between dose, blood con-
centrations, acute rejection prophylaxis and toxic-
ity are evolving and, therefore, are not yet well
published. On the basis of our experience in the
University of Texas-Houston transplant programme,
we have tried in this review to present more infor-
mation on therapeutic monitoring and emphasise
the importance of blood concentration monitoring,
as well as presenting current approaches to formu-
lation and dosage selection.
2. Analytical Assays
Sirolimus blood concentrations of 5 to 20 μg/L
display potent immunosuppression in large animal
models and in clinical practice.[8-10] Parent drug
concentrations seem to represent the critical indi-
ces for clinical effects, since there is no evidence
that metabolites have more than modest biological
activity (at most <10% of that of sirolimus).[11]
Thus, the methods used for therapeutic drug monitor-
ing must meet the following criteria: (i) specificity
for parent compound rather than metabolites; (ii)
detection sensitivity of 2 μg/L; (iii) readily avail-
able analytical equipment; (iv) reliable extraction
procedures and measurement techniques; and (v)
sample turnaround time within 24 hours. A panel
of experts[12] recommended that the analytical as-
say should also have the following performance
characteristics: (i) interday coefficient of variation
(%CV) of ≤10% at 5 μg/L and ≤5% at 40 μg/L
concentrations; (ii) detection range of 1 to 75 μg/L;
and (iii) slope of 0.9 to 1.1 and standard deviation
of the estimate <5 μg/L when compared with a val-
idated assay.
1. Chemical Characteristics
Sirolimus is a white crystalline solid with em-
pirical formula C56H89NO14, which melts at 183 to
185°C, is readily fat soluble and practically insol-
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Clin Pharmacokinet 2001; 40 (8)

Sirolimus
575
12
CH3
11
13
14
10
O
15
16
O
H
HO9
O
8
6
5
CH3
17
OCH3
4
7
N
18
19
2
3
O
36
H
O
20
1
21
22
38
41
34
CH3
OCH3
OH
35
37
39
40
33
O
OH
23
30
32
31
24
CH3
42
25
27
29
26
28
O
CH3
OCH3 CH3
CH3
Fig. 1. Chemical structure of sirolimus: (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,
23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-
10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaacyclohentriacontine-1,5,11,28,29(4H,6H,31H)
-pentone.
Because 95% of drug is sequestered in red blood
cells,[13] the preferred matrix for sirolimus measure-
ment is whole blood. Blood samples collected in
tubes containing EDTA as the anticoagulant are
stable up to 24 hours at room temperature, 7 days
at 2 to 8°C and 3 months at –20°C.[12]
(table I).[14,15] Unfortunately, MS technology has
the characteristics of being labour-intensive, tech-
nically difficult and expensive, which hinders its
routine clinical application, and it has only recently
become more available.
2.2 Liquid Chromatography with
Ultraviolet Detection
2.1 High Performance Liquid
Chromatography with Detection by
Tandem Mass Spectroscopy
Liquid chromatography with ultraviolet detec-
tion (LC/UV) specifically measures sirolimus in
whole blood at the 278nm wavelength (table
I).[16,19] Comparison of 385 paired determinations
by LC/UV and LC/MS-MS showed a correlation
coefficient of 0.943, regression line slope of 1.024,
and standard error of estimate of 2.87.[20] In this
High performance liquid chromatography with
detection by tandem mass spectroscopy (LC/MS-
MS) specifically measures sirolimus with a sensi-
tivity of 0.25 μg/L, linearity over the range of 0.25
to 250 μg/L, and an interday %CV of 19 to 1.4%
Table I. Assay methodologies for quantification of sirolimus
Assay
Sensitivity
(μg/L)
Linearity range
(μg/L)
Interday %CV
Cross-reactivity (parent +
metabolites/parent)
Reference
LC/MS-MS
LC/UV
RRA
0.25
1.0
1.0
0.25-250
1.0-50
2.5-40
3.0-30
1.4-19%
5.6-17%
5.9-12.9%
8.4-11%
1.0
1.0
1.26
1.42
14
16
17
18
MEIA
3.0
LC/MS-MS = high performance liquid chromatography with detection by tandem mass spectroscopy; LC/UV = high performance liquid
chromatography with ultraviolet detection; MEIA = microparticle enzyme immunoassay;[14] RRA = radioreceptor assay; %CV = coefficient
of variation.
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Clin Pharmacokinet 2001; 40 (8)

576
Mahalati & Kahan
a
containing sirolimus 5 to 80 μg/L, LC/UV showed
higher values than LC/MS-MS by 3 to 5.7 μg/L.[21]
The LC/UV method has been reported to have a
sensitivity of 1.0 μg/L, linearity over the 1.0 to 50
μg/L range and an interday %CV of 5.6 to 17%.[16,19]
Furthermore, LC/UV methodology is more readily
available and has successfully been used for thera-
peutic monitoring in clinical laboratories.[22]
70
60
50
40
30
20
10
0
2.3 Radioreceptor Assay
Radioreceptor assay (RRA), also called immuno-
philin-binding assay, is based on the affinity of parent
drug and some metabolites for a 52kD immuno-
philin binding protein.[23] The assay displays a sen-
sitivity of 1.0 μg/L, linearity over the 2.5 to 40 μg/L
range and %CV of 5.9 to 12.9% (table I).[17] Al-
though Goodyear et al.[23] reported an excellent
correlation between the results of RRAand LC/UV
(r = 0.977, slope of regression line 1.09), Davis et
al.[17] observed poorer correlation coefficients among
paired comparison of values from 51 blood sam-
ples in nonthrombocytopenic and thrombocytope-
nic patients (r = 0.706 and r = 0.806, respectively).
The 10 to 26% cross-reactivity of the binding assay
for sirolimus metabolites,[24] as detected by the de-
viation of RRA results from LC/UV values, did not
afford a better prediction of thrombocytopenia.[25]
Although RRA has the potential for semiautoma-
tion, it has not been developed into a clinical assay.
r = 0.943
0
10
20
30
40
50
60
70
LC/MS-MS (µg/L)
b
20
10
0
−10
−20
2.4 Microparticle Enzyme Immunoassay
0
10
20
30
40
50
60
An automated immunoassay using the IMx™
analyser (Abbott, N. Chicago, IL, USA) was used
for concentration measurements in the phase III
clinical trials, but was then withdrawn from further
use. The assay overestimates LC results by 42.5%
as a result of cross-reactivity with sirolimus meta-
bolites.[26] It shows an interday %CV of 8.4 to 11%
and a sensitivity of 3.0 μg/L (table I).[18] The slope
of the regression line of IMx™ compared with LC
values is 1.39, which is well outside the range rec-
ommended for a clinical assay. Although the
method has the advantage of ready availability,
easy methodology and fast turnaround time, it does
not meet the suggested criteria for therapeutic drug
Concentration (µg/L)
Fig. 2. Correlation between high performance liquid chromatogra-
phy with ultraviolet detection (LC/UV) and high performance liquid
chromatography with detection by tandem mass spectroscopy
(LC/MS-MS) measurements of sirolimus. (a) Correlation plot with
dotted lines showing 95% confidence limits; and (b) the ratio of
difference between estimates by each method as a function of
drug concentration (from Kahan et al.,[20] with permission).
large analysis, the majority of disparate samples
showed values within 4 μg/L of one another, with
no obvious bias of LC/UV values to be either
greater or less than those obtained by LC/MS-MS
(fig. 2). In a smaller cohort of 55 blood samples
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Clin Pharmacokinet 2001; 40 (8)

Sirolimus
577
monitoring, and clinical development is not ex-
pected.
cyclosporin and steroids revealed no association
between sex, age, bodyweight or ethnicity and ob-
served or dose-adjusted Cmax, Cmin or AUC, all
ss
3. Pharmacokinetics
of which showed significant intraindividual vari-
ability (%CV of 42.4 to 82.0%).[20]
The pharmacokinetic parameters of sirolimus
are summarised in table II.
The current marketed form of sirolimus is an
oil-based liquid available in 60 and 150ml bottles
and 1, 2 and 5mg sachets containing 1 mg/ml of the
drug. The tablet formulation, which offers greater
palatability and convenience of administration, is
expected to be available in mid-2001. In a phase
IIB trial, the 2 forms showed equal efficacy[33] and
similar pharmacokinetic behaviour to the liquid
preparation, except for an earlier and higher peak
concentration of the liquid formulation, with equal
overall exposure during the 24-hour dosage inter-
val.[34]
3.1 Absorption
The absolute bioavailability of sirolimus is un-
known. Based on the concentration data after a
small group of haemodialysis patients received the
drug intravenously (B.D. Kahan and J. Zimmer-
man, unpublished observations) versus the concen-
trations in stable renal transplant patients given
similar doses orally, the apparent oral bioavailabil-
ity has been estimated to be about 15%.[30] Esca-
lating single oral dose studies (3 to 21 mg/m2) in
the latter group receiving, in addition, cyclosporin
and corticosteroids showed peak whole blood con-
centrations (Cmax) of 14 to 344 μg/L, time to peak
concentration (tmax) of 0.5 to 3 hours (mean SD,
1.4 1.2 hours), only modest correlations (r =
0.59) between dose and Cmax or area under the con-
centration-time curve (AUC),[29] but a good corre-
lation (r2 = 0.85) of trough concentration prior to
Pharmacokinetic studies in 21 stable renal trans-
plant patients were performed on the last dose of
oral liquid formulation prior to, and at 2, 4 and 8
weeks after, conversion to the tablet form on a milli-
gram/milligram ratio.[35] There was no significant
difference in the AUC values before versus 2, 4 and
8 weeks after conversion, namely, 256 versus 205,
226 and 224 μg • h/L, respectively. Although Cmin
ss
the dose (Cmin ss) to AUC.[27,31] Thus, Cmin pro-
ss
values were not significantly different between
studies after administration of liquid versus tablet
forms, Cmax values were significantly lower with
the tablet form (37.1 versus 25.3, 24.9 and 26.7 μg/L,
vides a simple, useful index for therapeutic moni-
toring. Of note, analysis of a cohort of 150 kidney
transplant recipients treated de novo with sirolimus,
Table II. Summary of sirolimus pharmacokinetic parameters in stable renal transplant recipients concomitantly treated with cyclosporin and
prednisone (unless otherwise noted)
1
Dose
Centre
Assay
No. in
sample
16
22b
15
17
40
150
36
Dosage
tmax
(h)
1-6
0.81a
0.8-2.3
0.67-3
t ⁄ β
CL/F
Vss/F
Reference
2
(h)a
56.9
68.3
58.6
57
(L/h/kg)a
(L/kg)a
S
S
S
M
M
M
M
S
S
S
M
S
S
M
LC/MS-MS
LC/MS-MS
LC/MS-MS
3-15 mg/m2
15mg
3-21 mg/m2
3-34 mg/m2
0.5-6.5 mg/m2/12h 1.4a
0.5-15mg
3-15 mg/m2
0.281
0.323
27
28
29
30
31
20
32
0.147
0.208
30.6 L/h (510 ml/min)
8.9 L/h
8.3
12
LC/MS-MS
LC/UV
LC/MS-MS
62
1-2
63
462L
a
b
Mean value.
Healthy volunteers after fasting.
CL/F = apparent systemic clearance; LC/MS-MS = high performance liquid chromatography with tandem mass spectrometry; LC/UV = high
performance liquid chromatography with ultraviolet detection; M = multiple; S = single; tmax = time to reach peak plasma drug concentration;
1
t
⁄ β = elimination half-life; Vss/F = apparent volume of distribution at steady state.
2
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Clin Pharmacokinet 2001; 40 (8)

578
Mahalati & Kahan
50
40
30
20
10
0
Liquid
Tablet
respectively; p < 0.05; fig. 3). Of note, the mean
%CV of the dose-corrected AUC values was lower
when patients received the tablet than the liquid
formulation.[35]
Week 2
Week 4
A nested group of 24 de novo kidney transplant
patients had full pharmacokinetic profiles on siro-
limus oral solution (n = 13) or tablet form (n = 11),
which showed similar C0, AUC and Cmax but sig-
nificantly longer tmax in patients taking the tablet
form (5.8 4.1 vs 2.0 1.2h; p < 0.05).[34] Again,
there was lower interpatient variability in patients
taking the tablet form. Another recent multicentre,
randomised study in de novo kidney transplant re-
cipients confirmed the results of the previous study,
with tmax being the only pharmacokinetic parame-
ter significantly different between patients on the
oral solution versus the tablet form (2.12 0.84 vs
3.46 2.40h; p = 0.054).[36] In 22 healthy adult
volunteers, a high fat meal decreased sirolimus
AUC by 35%.[28] It is recommended that patients
take the drug consistently with or without food to
reduce fluctuations in drug exposure. Furthermore,
concomitant administration with the microemulsion
but not the oil-based formulation of cyclosporin
promotes sirolimus absorption.[37]
50
40
30
20
10
0
50
40
30
20
10
0
Week 8
0
2
4
6
8
10
12
Time after administration (h)
Fig. 3. Pharmacokinetic profiles of mean values of whole blood
sirolimus concentrations of 21 patients over 12 hours after admin-
istration of the last dose of the liquid formulation of sirolimus and
at 2, 4 and 8 weeks after conversion to the tablet formulation of
sirolimus (from Kelly et al.,[35] with permission).
In similarfashion to cyclosporin, overall sirolimus
absorption is probably affected by the activity of
P-glycoprotein as well as intestinal cytochrome
P450 (CYP) activity.[38] The 2 compounds are likely
to cross-inhibit these activities, possibly account-
ing for the pharmacokinetic interaction as well as
the interpatient variability at the absorptive inter-
face.
of sirolimus was 34.5 1,[31] with significant inter-
:
individual variability (CV% 52.3, range 10 to 70).
In the plasma compartment, a smaller proportion
of sirolimus (compared with cyclosporin) is bound
to lipoproteins (40%), although this ratio increases
with increasing sirolimus concentrations. The dis-
tribution of sirolimus among lipoprotein fractions
has not yet been reported, although it is known that
the metabolic effects of sirolimus increase the con-
tent of high, low, intermediate and very low density
lipoproteins.[40] Among the 60% in the free fraction,
only a small proportion (about 4%) is bound to sol-
uble plasma proteins.[13] Thus, whole blood is con-
sidered the appropriate matrix for therapeutic drug
monitoring.
3.2 Distribution
In human whole blood, sirolimus is distributed
among red blood cells (94.5%), plasma (3.1%),
lymphocytes (1.01%) and granulocytes (1.0%). In
contrast to tacrolimus and cyclosporin, the distribu-
tion is not temperature- orconcentration-dependent.[13]
The sequestration of sirolimus, like tacrolimus, in
red blood cells is believed to be at least partially
due to their abundant content of immunophilins.[39]
The mean blood-to-plasma ratio in 36 stable renal
transplant recipients treated with a single oral dose
Because of its hydrophobic nature, sirolimus is
widely distributed in lipid membranes of body tis-
sues as well as erythrocytes, showing a large ap-
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Clin Pharmacokinet 2001; 40 (8)

Sirolimus
579
parent volume of distribution (5.6 to 16.7 L/kg).[12,32]
Data from rats support this observation. Following
14 days of intravenous or oral administration,
spleen, kidney, liver, intestine and heart tissue-to-
blood partition coefficients were as high as 40.[41]
Because the tissue distribution of sirolimus has not
formally been studied in humans, the possible re-
lationship of these concentrations to the efficacy
and toxicity of the drug is currently unknown.
pivotal phase III study (Global 302) among 212
ss
patients receiving 2 mg/day, the Cmin over the
6-month period was 2.34 to 31.30 μg/L; the values
for patients on 5 mg/day were 5.95 to 50.90
μg/L.[46] Presumably, the primary clearance route
for sirolimus metabolites is biliary: 91% of the
transformation products after administration to
healthy volunteers of a single dose of radioactive
sirolimus were found in faeces, in contrast to 2.2%
excreted in urine.[47] As with cyclosporin and
tacrolimus, hepatic dysfunction results in increased
concentrations of sirolimus and its metabolites.
More than 16 metabolites have been identified
in the bile of rats receiving sirolimus.[48] In hu-
mans, trough whole blood samples contain 56
9% of drug-derived compounds as metabolites,
particularly the 12-hydroxy-, 16-O-demethyl-, 39-
O-demethyl-, 27,39-O-di-demethyl- and dihydroxy-
sirolimus (fig. 4), which form 71.8 68%, 35
42%, 20 20% and 20 31% of total metabolites,
respectively.[14] Although sirolimus metabolites
seem to display less than 10% of the activity of
the parent compound,[11,49,50] it is possible that de-
tailed characterisation of the toxic versus immuno-
suppressive effects of sirolimus metabolites may
provide insights for therapeutic drug monitoring.
3.3 Metabolism and Elimination
The large interindividual variability in cyclo-
sporin biotransformation is related to 8.5- and 9.4-
fold variability in enterocyte P-glycoprotein and
CYP3A4 content, respectively,[42,43] and similar
interindividual variability in the actions of these
systems on sirolimus biotransformation[44] and
efflux can be expected.[43,45] Other CYP family
members potentially play a role in sirolimus meta-
bolism; however, there are no studies documenting
their participation.
In 16 stable renal transplant recipients receiving
cyclosporin and prednisone at the time of admin-
istration of a single sirolimus dose, there was an
8-fold difference in apparent clearance (0.042 to
0.339 L/h/kg) and a range of terminal half-lives of
43.8 to 86.5 hours.[27] Among 40 stable renal trans-
plant recipients who received a 14-day course of
sirolimus in addition to cyclosporin and prednisone,
there was 4.5-fold variation in apparent clearance
(0.090 to 0.416 L/h/kg, mean 0.210 L/h/kg) and a
terminal half-life of 62 12 hours.[31] The long
terminal half-life of the drug necessitates a loading
dose (2.56 0.70 × maintenance dose) to achieve
steady-state concentrations rapidly,[31] and also al-
lows a once daily administration schedule, which
is more convenient for the patient than the twice
daily regimen generally used for calcineurin inhib-
itors; this advantage may improve compliance with
the therapeutic regimen. The tablet form of siro-
limus appears to have similar apparent oral clear-
ance to the oral solution.[34,36]
3.4 Drug Interactions
Drugs affecting CYP3A4 or P-glycoprotein levels
or activities would be expected to alter sirolimus
pharmacokinetics. Diltiazem and ketoconazole in-
creased sirolimus AUC by 60 and 990%, respec-
tively, whereas rifamycin reduced AUC by 82%.[46]
Simultaneous administration of cyclosporin in the
microemulsion, but not the oil-based, formulation
increased sirolimus AUC by 50%, but sirolimus
did not alter cyclosporin exposure.[37] In rats, con-
comitant oral administration of cyclosporin and
sirolimus increased both the blood and the tissue
concentrations of both drugs,[51] and, in phase III
studies, patients receiving sirolimus required
lower cyclosporin dosages to achieve similar target
cyclosporin concentrations.[52] The nature, extent
and clinical implications of the pharmacokinetic
Variations in drug clearance and absorption
rates result in a wide range of sirolimus Cmin ss val-
ues among patients receiving the same dose. In a
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Clin Pharmacokinet 2001; 40 (8)

580
Mahalati & Kahan
12
O
12
CH
8
11
10
CH
8
3
11
10
3
13
14
13
14
O
O
15
16
15
16
O
3
9
9
H
HO
H
HO
6
5
3
CH
6
5
4
3
CH
19
17
3
3
17
OH
O
OCH
O
4
7
N
7
N
18
18
19
2
2
H
O
H
O
20
20
1
1
21
22
23
O
21
22
23
O
38
41
38
34
34
CH
3
OCH
OH
CH
35
37
39
40
3
OH
OH
35
37
39
40
3
33
32
36
33
32
36
O
OH
28
O
OH
30
30
CH
24
25
27
29
42
CH
24
31
25
29
31
42
3
27
3
26
26
28
O
O
41
CH
OCH
CH
CH
3
CH
OCH
CH
CH
3
3
3
3
3
3
3
16-O-demethyl-sirolimus
39-O-demethyl-sirolimus
12
12
CH
CH
3
11
10
3
11
10
13
14
13
14
O
O
15
O
15
16
O
9
9
H
HO
O
H
HO
O
16
17
8
6
5
3
8
CH
19
CH
6
5
3
3
17
OCH
3
OCH
3
4
N7
7
4
N
18
18
19
2
2
3
H
O
H
O
20
20
1
1
21
O
21
O
38
41
38
22
23
34
22
23
34
CH
3
OH
OH
35
37
39
40
CH
OCH
3
35
37
39
40
3
33
32
36
36
O
OH
33
32
O
OH
30
30
29
31
CH
25
27
42
CH
3
24
24
25
27
29
31
42
3
26
28
26
28
OCH
O
O
OH
41
CH
CH
CH
3
CH
CH
CH
3
3
3
OH
3
3
3
27-39-O-di-demethyl-sirolimus
Fig. 4. Chemical structures of sirolimus metabolites.
Di-hydroxy-sirolimus
interactionsbetweensirolimusandcyclosporinre-
quire further investigation.
occurrence and severity of adverse effects of siro-
limus correlate with blood concentrations.[8,54] In a
phase I/II study of 40 de novo mismatched living
Administration of a 2-week course of 1 to 13
mg/m2 sirolimus to 40 stable renal transplant pa-
tients resulted in a significant increase in predni-
solone AUC (mean ratio 1.27; p = 0.0001).[53]
The clinical significance of this finding needs fur-
ther study.
ss
donor kidney transplant recipients, Cmin values
>15 μg/L (LC/UV assay) were associated with ad-
verse reactions of increased triglyceride levels or
reduced haemoglobin, leucocyte and particularly
platelet counts (fig. 5).[55] In a retrospective single-
centre review of 150 kidney transplant recipients
treated de novo with a sirolimus/cyclosporin com-
bination, sirolimus Cmin ss values >15 μg/L (LC/UV
assay) had a positive predictive value for hypertri-
4. Therapeutic Drug Monitoring
Both experimental animal and clinical data sug-
gest that the immunosuppressive efficacy and the
© Adis International Limited. All rights reserved.
Clin Pharmacokinet 2001; 40 (8)

Sirolimus
581
ss
glyceridaemia (>300 mg/dl), thrombocytopenia
(<100 000/mm3) and leucopenia (<4000/mm3).[20]
Furthermore, dose-corrected Cmin values <1.7
The appropriate sirolimus Cmin for acute re-
jection episode prophylaxis is a function of the
concomitant immunosuppressive regimen (table
III). When used as base therapy with azathioprine
ss
μg/L/mg were associated with a 3.6-fold increase
ss
ss
in, and observed Cmin values >5 μg/L had an
and prednisone, a regimen stipulating initial Cmin
89.5% negative predictive value for, the occur-
rence of acute rejection episodes (fig. 6). Thus it
appears that, when sirolimus is used in addition to
cyclosporin and prednisone, a therapeutic concentra-
tion range of 5 to 15 μg/L is associated with pro-
tection from acute rejection episodes and adverse
effects. Sirolimus allows a 50% reduction in cyclo-
sporin exposure,[56] a property that can be especially
useful in patients who receive cadaveric renal
grafts, which tend to show slow recovery of renal
function.
values equal to 30 μg/L during the first 2 months,
and 15 μg/L(LC/UV assay) thereafter, led to a 41%
rate of acute rejection episodes among 41 cadav-
eric kidney transplant recipients.[57] When com-
bined with mycophenolate mofetil and prednisone,
this sirolimus regimen was associated with a
27.5% rate of acute rejection episodes among 40
cadaveric renal transplant recipients.[58] Indeed,
ss
the combination of sirolimus (Cmin of 10 to 20
μg/L; LC/UV assay) and basiliximab with late in-
troduction of low dosage cyclosporin has provided
a
b
100
8.10
9.72
80
60
40
20
0
6.48
7.56
8.64
10.26
11.34
11.88
12.96
14.04
10.80
11.88
12.96
14.04
14.58
15.66
c
d
100
80
60
40
20
0
5.94
7.02
8.10
3.78
5.40
6.48
7.56
8.64
9.72
11.34
12.42
13.50
9.72
10.80
11.88
0
20
40
60
80
0
20
40
60
80
False-positive rate
Fig. 5. Receiver operating characteristic functions to predict the correlation between trough steady-state concentrations (Cmin ss) and
sirolimus-induced adverse drug reactions. (a) Thrombocytopenia (<100 000/mm3); (b) leucopenia (<4000/mm3); (c) hypertri-
glyceridaemia (>400 mg/dl); (d) hypercholesterolaemia (>240 mg/dl) [from Kahan et al.,[20] with permission].
© Adis International Limited. All rights reserved.
Clin Pharmacokinet 2001; 40 (8)

582
Mahalati & Kahan
after a dosage change. Thus, daily concentration
monitoring is not necessary; the first sirolimus
measurements should not be obtained before day 4
after inception of, or change in, therapy. Thereafter,
a
100
80
60
40
20
0
1.04
1.30
1.56
1.82
2.08
2.21
2.47
2.73
ss
we recommend monitoring Cmin weekly for the
first month and bi-weekly for the next month, tar-
geting a 5 to 15 μg/L range if cyclosporin is being
used concomitantly at Cmin ss concentrations of 75
to 150 μg/L. If the patient fails to attain these val-
ues despite a dosage of 20 mg/day, a full pharmaco-
kinetic study should be performed to assess
whether the defect is due to limited absorption or
ss
rapid clearance rates. After the second month, Cmin
b
estimates are necessary only if warranted clinically:
namely, upon changes in or addition to the thera-
peutic regimen of a drug that affects CYP3A4 bio-
transformation or because of suspicion of unusual
circumstances or noncompliance, gastrointestinal
disturbances, or exaggerated toxicity.
100
272.62
296.68
320.74
344.80
368.86
384.90
408.96
425.00
80
60
40
20
0
The solid formulation has been approved by the
US Food and Drug Administration (FDA) for use
in kidney transplant recipients. The solid form
showed similar pharmacokinetic behaviour, except
for lower Cmax, to the liquid preparation in stable
renal transplant recipients (section 3.1). Conversion
from one formulation to the other was not associ-
ated with any significant adverse effects or with
any acute rejection episodes.[35]
In a nonblind, multicentre, randomised trial,
477 de novo kidney transplant recipients receiving
2 mg/day of either oral solution or tablet form of
sirolimus in addition to cyclosporin and corticoste-
roids showed similar efficacy and adverse effect
profiles.[33] The incidences of acute rejection (21
vs 19%), graft survival (94 vs 91%) and patient
survival (97 vs 98%) were similar between the 2
groups. The main adverse effects were anaemia, de-
crease in platelet count and increase in triglyceride
and cholesterol levels, which occurred with similar
frequency in both groups.
0
10 20 30 40 50 60 70 80 90
False-positive rate
Fig. 6. Receiver operating characteristic functions to predict the
occurrence of an acute rejection episode. (a) Use of dose-cor-
rected trough steady-state concentration (Cmin ss/mg); (b) use of
dose-corrected area under the concentration-time curve (AUC/
mg) [from Kahan et al.,[20] with permission].
excellent prophylaxis of acute rejection episodes and
renal function for primary, non–African-American
recipients of cadaveric kidney transplants that
displayed delayed graft function.[59,60] In purely
Caucasian low-risk liver and kidney-pancreas
transplant recipients, Cmin ss of 6 to 12 μg/L (IMx™
assay) in combination with low dosage tacrolimus
has been reported to yield low rates of acute rejec-
tion episodes and toxicity.[10]
The appropriate regimen for long term drug
monitoring has not been established. Because of
the long half-life and extensive tissue distribution
of the drug, steady-state concentrations are not
reached before day 6 after initiation of therapy or
5. Conclusion
Although structurally similar to tacrolimus, siro-
limus has a novel mechanism of action, which leads
to synergy with cyclosporin. The long half-life of
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Clin Pharmacokinet 2001; 40 (8)

Sirolimus
583
Table III. Sirolimus concentrations and acute rejection prophylaxis in combination with other immunosuppressive agents
Concomitant immunosuppressants with
sirolimus
No. in
sample
Organ
Sirolimus target
concentration (μg/L) rate (%)
Acute rejection
References
Prednisone + azathioprine
Prednisone + mycophenolate mofetil
Prednisone + cyclosporin
41
40
150
6
Kidney
Kidney
Kidney
Kidney
30
30
5-15
10-20
41.0
27.5
10.5
7.0
57
58
20
59,60
Prednisone + basiliximab + delayed low
dosage cyclosporin
Prednisone + tacrolimus
32
Liver, kidney/pancreas 6-12
9.0
10
the drug necessitates a loading dose to achieve
therapeutic concentrations quickly, and also allows
for once daily administration. Highly variable ab-
sorption and metabolism of the drug result in large
differences in blood concentrations among patients
receiving the same dose. Efficacy for the prevention
of acute rejection episodes, and the rate of common
adverse effects (thrombocytopenia, leucopenia and
hypertriglyceridaemia), are concentration-dependent.
Thus, despite the FDA-mandated pivotal blinded
trials using fixed dosages of sirolimus in conjunc-
tion with full exposure to cyclosporin and pre-
dnisone, it is now recognised that therapy in renal
transplant recipients is optimised by marked reduc-
tions in the dosages of immunosuppressive agents,
a strategy that demands therapeutic drug monitor-
ing.[30] The excellent correlation between Cmin and
AUC makes the former a simple and reliable index
for monitoring sirolimus exposure. However, auto-
mated assays to measure whole blood concentra-
tions are not available. Although the addition of
sirolimus to the current armamentarium of immuno-
suppressive drugs has resulted in novel approaches
to reduce or avoid the nephrotoxicity caused by
calcineurin inhibitors, the effect of these regimens
or of pharmacokinetic parameters on long term
graft survival, as evidenced by the incidence of
chronic rejection, is not yet known. The pharmaco-
kinetic behaviour and therapeutic drug monitoring
guidelines for sirolimus in other solid organ trans-
plant recipients await further investigation.
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