Full text of DOI:10.2165/00044011-200121020-00005

Clin Drug Invest 2001; 21 (2): 129-136
1173-2563/01/0002-0129/$22.00/0
CLINICAL PHARMACOKINETICS
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Multiple-Dose Pharmacokinetics of Atrasentan,
an Endothelin-A Receptor Antagonist
Sandeep Dutta,1 Emil Samara,1 Wayne Lam,1 G.R. Granneman,1 Philip T. Leese 2 and
R.J. Padley1
1
2
Abbott Laboratories, Abbott Park, Illinois, USA
Innovex, Inc., Lenexa, Kansas, USA
Abstract
Objective: To determine the single- and multiple-dose pharmacokinetics of
atrasentan, a highly selective endothelin-A receptor antagonist that is currently
being investigated for the treatment of prostate cancer and cardiovascular dis-
orders.
Design: Phase I, randomised, placebo-controlled, double-blind, single- and
multiple-dose study of orally administered atrasentan.
Methods: Single daily oral doses of 1, 5, 10, 15, 20, 25, 30 or 40mg of atrasentan
or placebo were administered to healthy male volunteers (n = 72; six active and
three placebo per drug administration group) on study day 1 and days 3 to 9.
Atrasentan plasma concentration-time profiles for day 1 and day 9 were used to
assess atrasentan pharmacokinetics.
Results: Except for the 1mg group, atrasentan plasma concentrations increased
rapidly after single and multiple administration, declining thereafter biexponen-
tially with a study-wide harmonic mean (pseudo-SD) half-life of 21 (12) hours
and mean (SD) apparent total body clearance (CL/F) of 28 (9.8) L/h. For the
1mg group, there was no apparent distribution phase and the absorption was
slower. Drug administration in the 40mg group was discontinued prematurely
because of adverse events. Except for lower-than-predicted maximum plasma
concentration (Cmax) values for the 1mg group, drug exposure (Cmax, trough
concentration and area under the concentration-time curve) increased linearly
with dose, and CL/F values were similar across groups, after single- and
multiple-dose administration. Steady state was reached within 4 days of drug
administration.
Conclusion: The pharmacokinetics of atrasentan are dose- and time-independent
after single- and multiple-dose administration over the range of 1 to 30 mg/day.

130
Dutta et al.
Endothelins are a family of three paracrine/
obtained from each participant after the purpose
and nature of the study had been explained. Partic-
ipants were screened for eligibility based upon the
results of medical history, physical examination,
laboratory profile, chest x-ray and electrocardio-
gram.
autocrine peptides (ET-1, ET-2 and ET-3) produced
in a variety of tissues where they apparently act as
modulators of vasomotor tone, cell proliferation
and protein synthesis.[1-3] Two types of endothelin
receptors, ETA and ETB, have been identified.[4]
ETA receptors have a high affinity for ET-1 and
ET-2, whereas ETB receptors have equal affinity
for all of the ET-related peptides.[4] ETA receptors
are primarily responsible for ET-1-mediated vaso-
constriction and cell proliferation.[3,4] ETB recep-
tors can contribute to the vasomotor tone and are
thought to provide a mechanism for the clearance
of endothelins as well as feedback regulation of
endothelin synthesis and secretion.[4]
Atrasentan (ABT-627) is an endothelin ant-
agonist with approximately 1800-fold selectivity
for the ETA-receptor. In a dose-dependent manner,
atrasentan inhibits the increase in arterial blood
pressure induced by ET-1. In addition, in several
animal models, atrasentan and its racemate,
A-127722, have yielded promising results that
indicate that antagonism of the effects of ET-1 may
be beneficial in the pathophysiological states of
congestive heart failure,[5] pulmonary hyperten-
sion,[6] essential hypertension, restenosis,[7] renal
failure[8] and cancer.[9] Accordingly, atrasentan is
being developed to evaluate its therapeutic utility
in several of these disorders. The objective of this
study was to evaluate the pharmacokinetics and
safety of multiple doses of atrasentan, administered
once daily. Results of this study were used to guide
the selection of doses for phase II studies. This is
the first report of the multiple-dose pharmaco-
kinetics of atrasentan in humans.
Study Design
This was a Phase I, randomised, placebo-
controlled, double-blind, single and multiple oral
dose study of atrasentan. Seventy-two healthy
males were equally divided into eight drug admin-
istration groups. A randomisation schedule was
computer-generated for each drug administration
group prior to the start of the study. Within each
drug administration group, the participants were
assigned, in a 2:1 ratio, to receive either atrasentran
or matching placebo according to the randomisa-
tion schedule. The drug administration schedules
were designed such that successively higher
doses were administered after safety had been
determined for the previous group. Single daily
oral doses of 1, 5, 10, 15, 20, 25, 30 or 40mg of
atrasentan or placebo were administered to partic-
ipants on study day 1 and days 3 through 9. No dose
was administered on day 2. Atrasentan was formu-
lated by Abbott Laboratories as a 1 mg/ml oral so-
lution in a vehicle of 50% glycerin, 14% alcohol
and water. The vehicle was utilised as placebo.
Participants from each dose group were con-
fined to the research unit from day –1 to day 13.
Normal research unit meals were served during
confinement and participants were not permitted to
engage in any strenuous activity or exercise during
the study. Drug administration was accomplished
after an 8-hour fast and the first post-dose meal
was consumed approximately 2 hours after drug
administration. Participants were asked to abstain
from caffeine starting 3 days prior to confinement
to the research unit on day –1 until they were re-
leased from the unit on study day 13. Blood
samples were collected after the first dose on day
1 over a 48-hour interval and after the last dose on
day 9 over a 96-hour interval for determination of
atrasentan plasma concentrations.
Participants and Methods
Participants
A total of 72 healthy adult nonsmoker male
volunteers were enrolled in the study. The partici-
pants’ average (SD) age and bodyweight were 31
(8.2) years and 82.4 (10.6) kg, respectively. The
ethics committee at Innovex, Inc. approved the
study protocol. Written informed consent was
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Clin Drug Invest 2001; 21 (2)

Atrasentan Multiple-Dose Pharmacokinetics
131
Analytical Methodology
more appropriate for the 103 range in observed
concentrations. The data variance was assumed to
be similar to analytical error, with a coefficient of
variation (CV) of 10% at or below 1 μg/L and 5%
at 250 μg/L.
Atrasentan plasma concentrations were deter-
mined using a validated HPLC method with fluor-
escence detection.[10,11] The assay was specific and
sensitive with a lower quantifiable limit for
atrasentan of 0.21 μg/L from 1ml of plasma. The
assay was unbiased with coefficients of variation
(CVs) below 10%.
Statistical Analyses
Dose proportionality and linear kinetics were
assessed by analyses of covariance (ANCOVAs)
for day 1 (first dose) and day 9 (last dose) pharma-
cokinetic parameters. The pharmacokinetic para-
meters analysed included tmax, β and dose-
normalised values of Cmax, Cmin and AUC. The
model included classification by dose level and
had baseline bodyweight and age as co-variates.
Because of the unusual concentration versus time
profiles in the 1mg dose group, similar analyses
were performed after excluding data from the 1mg
dose group.
To assess attainment of steady state after
multiple doses of atrasentan, an analysis of vari-
ance (ANOVA) was performed on 0-hour pre-dose
concentrations (Cmin) on days 7 and 9. An ANOVA
was also performed on the change in dose-
normalised AUC from the first dose (AUC∞/D) to
the last dose (AUC24h/D). PROC GLM of SAS
version 6.12 was used for the ANCOVA and
ANOVAmodels, and type III sums of squares were
used for all tests of hypotheses. A p-value equal to
or less than 0.05 was considered statistically
significant.
Pharmacokinetic Analyses
Noncompartmental Analysis
Atrasentan pharmacokinetic parameters for the
first and last doses were determined using standard
noncompartmental methods.[12] For the first and
last dose interval, the following parameters were
determined: maximum observed concentration
(Cmax), time to Cmax (tmax), area under the plasma
concentration versus time curve (AUC) calculated
by the trapezoidal rule, apparent total body clear-
ance (CL/F) derived as dose/AUC, terminal phase
elimination rate constant (β) and elimination half-
1
life (t ⁄ β) calculated as ln(2)/β. Due to the short
2
collection period, β was not calculated after the
first dose administration except for the 40mg
group, where no steady-state data were available.
For calculation of single-dose AUC to infinity
(AUC∞), the extrapolation from the last measur-
able concentration was calculated as the quotient
of the last measurable concentration on day 2 and
β determined after administration of the last dose.
Additionally, pre-dose plasma concentrations
(Cmin) were determined on days 7, 8 and 9 (pre-
dose samples) and day 10 (24-hour sample of day 9).
Results
Mean atrasentan plasma concentration-time
profiles obtained after single- and multiple-dose
administration are shown in figure 1. Except for
the 1mg group, atrasentan plasma concentrations
increased rapidly after single- and multiple-dose
administration, reaching maximum plasma con-
centrations within 1 hour, declining thereafter
biexponentially. The absorption after the admini-
stration of the 1mg dose was slower and the
distribution phase was not apparent. Mean (SD)
atrasentan pharmacokinetic parameters are pre-
sented in table I. Drug administration in the 40mg
Parametric Modelling
A two-compartment open model with first-
order absorption into and first-order elimination
from the central compartment, and first-order
intercompartmental transfer, was used to charac-
terise atrasentan plasma concentration-time pro-
files. The pharmacokinetic model was fitted to the
mean plasma concentration-time data from the eight
drug administration groups using ADAPT II.[13]
Unweighted and mixed/proportional weighting
schemes were investigated, with the latter proving
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Clin Drug Invest 2001; 21 (2)

132
Dutta et al.
group was discontinued prematurely because of the
adverse event of headache.
for the noticeably lower value for the 1mg group.
The same was true for Cmax/D on day 9. Indeed the
dose effect was significant, both for days 1 and 9
(p = 0.016 and 0.029, respectively). However,
when data from the 1mg group were excluded,
the dose effect was not statistically significant
(p > 0.2).
Since there was no statistically significant effect
due to age, this covariate was dropped from the
statistical model. Bodyweight was not a significant
covariate (p > 0.05) for all pharmacokinetic para-
meters tested except for dose-normalised AUC∞
(p = 0.016). This may be due to randomness since
it was significant for single-dose administration
but not at steady state.
Time to Maximum Plasma Concentration
Maximum Plasma Concentration
Except for the 1mg group, maximum plasma
concentrations were attained within 1 hour after
administration in all participants. For the 1mg
group, after an initial increase in the concentrations
within the first few hours after drug administration,
secondary peaks were observed at later times.
The mean Cmax values obtained after single and
multiple doses of 1 to 40mg increased linearly with
dose (r2 > 0.87; fig. 2, top panel). The mean dose-
normalised Cmax values (Cmax/D) after single-dose
administration were similar for all groups except
Table I. Atrasentan pharmacokinetic parameters
Dose (mg)
Single dose
Multiple dose
1
Cmax
(μg/L)
tmax
(h)
AUC24h
(μg/L • h) (μg/L • h) (L/h)
AUC∞
CL/F
Cmax
(μg/L)
tmax
(h)
Cmin
AUC24h
t ⁄ β
CL/F
(L/h)
2
(μg/L)a
(μg/L • h) (h)b
1
5
Mean
SD
1.5
1.3
26
4.9
9.5
0.3
0.1
0.4
0.3
0.3
0.1
0.3
0.1
0.5
0.1
0.5
0.0
0.6
0.2
17
13
52
24
24
14
25
2.6
1.9
25
6.4
5.3
0.3
0.1
0.5
0.3
0.3
0.1
0.5
0.3
0.5
0.1
0.5
0.1
1.7
1.9
4.1
2.5
7.8
0.93
8.7
1.8
11
40
28
37
12
25
37
24
27
10
33
13
32
5.7
29
6.8
25
7.3
29
6.1
Mean
SD
120
33
220
69
210
81
14
8.4
28
3.7
30
7.9
28
6.9
27
6.3
25
3.5
26
6.3
4.7
46
6.3
25
4.0
10
15
20
25
30
40
Mean
SD
49
190
26
370
52
330
86
24
17
Mean
SD
97
330
110
470
98
530
170
740
200
960
220
1200
180
1600
430
90
490
100
720
190
1100
440
1100
240
13
12
20
57
26
Mean
SD
130
42
140
50
3.0
18
4.7
21
4.0
22
6.2
20c
3.9
Mean
SD
130
37
600
150
750
78
190
97
4.8
19
Mean
SD
200
61
220
92
2.9
Mean
SD
170
46
1000
170
a
b
c
Day 9, pre-dose concentration.
Reported as harmonic mean and pseudo-SD.
Calculated from the single-dose data.
AUC∞ = area under the plasma concentration-time curve from zero to infinity; AUC24h = area under the plasma concentration-time curve to
24 hours; Cmax = maximum plasma concentration; Cmin = trough (pre-dose) plasma concentration; CL/F = apparent total body clearance;
1
t
max = time to Cmax; t ⁄ β = elimination half-life.
2
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Clin Drug Invest 2001; 21 (2)

Atrasentan Multiple-Dose Pharmacokinetics
133
Furthermore, the difference between day 9 AUC24h
and first-dose AUC∞, excluding the 1mg dose
group, was not statistically significant (p = 0.212).
These results indicate that the pharmacokinetics of
atrasentan are time-independent in the dosage
range of 1 to 30 mg/day.
CL/F was similar after single- and multiple-
dose administration, averaging 27 (SD 12) and 30
(SD 12) L/h for days 1 and 9, respectively, suggest-
ing that the CL/F of atrasentan is dose- and time-
1mg
5mg
10mg
15mg
20mg
25mg
30mg
40mg
500
Day 1
200
100
50
20
10
5
2
1
0.5
0.2
0.1
0
6
12
18
24
30
36
42
48
a
500
Day 9
300
Day 1
200
100
50
Day 9
250
200
20
10
5
150
100
50
2
1
0.5
0.2
0.1
0
0
12
24
36
48
60
72
84
96
b
Time (h)
1800
Day 1 AUC24h
1600
1400
1200
1000
800
600
400
200
0
Day 1 AUC∞
Day 9 AUC24h
Fig. 1. Mean atrasentan plasma concentration-time profiles
obtained after single- and multiple-dose administration of
atrasentan.
Area Under the Concentration-Time Curve
and Apparent Clearance
0
5
10
15
20
25
30
35
40
Atrasentan dose (mg)
The mean AUC values increased dose-propor-
tionally (r2 > 0.96; fig. 2, bottom panel). The dose
effect was not significant (p > 0.149) for dose-
normalised AUC values after single- and multiple-
dose administration, indicating that atrasentan
pharmacokinetics are dose-independent in the dose
range of 1 to 30mg.
The average AUC∞ values obtained after
single-dose administration were comparable to the
AUC24h values obtained after multiple-dose
administration in all groups (fig. 2, lower panel).
Fig. 2. Mean maximum concentration (Cmax) [a] and area un-
der the concentration-time curve (AUC) [b] values obtained
after single (day 1) and multiple once-daily (day 9) administra-
tion of atrasentan. The lines represent the linear regression
of the Cmax or AUC values versus atrasentan dose.
Day 1 Cmax (continuous line), y = 9.26 + 4.97x (r2 = 0.877);
day 9 Cmax (dotted line), y = –17.2 + 7.89x (r2 = 0.987).
Day 1 AUC24h (continuous line), y = –32.4 + 25.6x (r2 = 0.996);
day 1 AUC∞ (dotted line), y = –23.9 + 40.6x (r2 = 0.994);
day 9 AUC24h (dashed line), y = –20.8 + 38.9x (r2 = 0.966).
AUC∞ = area under the plasma concentration-time curve from
zero to infinity; AUC24h = area under the plasma concentration-
time curve to 24 hours.
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Clin Drug Invest 2001; 21 (2)

134
Dutta et al.
statistical analysis for β. Except for the 1mg group,
the harmonic mean half-life obtained on day 9
ranged from 13 to 25 hours. The half-life for the
1mg group was higher, with a harmonic mean of
37 hours. The analysis for β found the test statistic
for dose to be not significant (p = 0.064). The
study-wide harmonic mean (pseudo-SD) half-life
was 21 (12) hours.
25
20
15
10
5
Day 7
Day 8
Day 9
Day 10
Parametric Modelling
0
A two-compartment open model optimally
characterised atrasentan plasma concentration-
time data. Observed atrasentan plasma con-
centrations versus those predicted by the two-
compartment model are shown in figure 4. The
model-estimated pharmacokinetic parameters, i.e.
absorption rate constant (ka), volume of the central
compartment (Vc/F), volume of the peripheral
compartment (Vp/F), clearance (CL/F) and distri-
bution clearance (CLd/F), are presented in table II.
Initially, a single ka was estimated for all groups.
However, the plasma concentration-time profiles
and noncompartmental analyses suggested that the
rate of absorption was substantially slower for the
1mg group compared with the higher dose groups.
Subsequently, separate absorption rate constants
0
5
10
15
20
25
30
Atrasentan dose (mg)
Fig. 3. Mean trough (pre-dose) concentration (Cmin) versus
atrasentan dose. Days 7, 8, 9 and 10 represent 4, 5, 6 and 7
consecutive daily doses, respectively. The continuous line re-
presents the linear regression of the data characterised by the
equation y = 1.179 + 0.618x (r2 = 0.952).
independent. There was no indication of any devi-
ation from linear pharmacokinetic behaviour after
7 days of daily drug administration. The study-
wide mean CL/F was 28 (SD 9.8) L/h.
Trough Concentration
The mean Cmin values increased linearly with
dose (r2 > 0.95; fig. 3). The mean dose-normalised
Cmin values after multiple-dose administration
were similar for all groups. The dose effect was not
statistically significant (p > 0.14) for day 9 dose-
225
200
175
150
normalised Cmin
.
The average Cmin values were similar for days
7, 8, 9 and 10 (fig. 3), suggesting that steady state
was predictably reached within 4 days of daily drug
administration. Indeed, the ANOVA for dose-
normalised Cmin revealed that the difference be-
tween day 7 and day 9 was not statistically signif-
icant (p = 0.865).
125
100
75
50
25
0
0
25 50 75 100 125 150 175 200 225
Predicted plasma concentration (μg/L)
Half-Life
Fig. 4. Observed atrasentan plasma concentrations versus
those predicted by the two-compartment model. The continuous
line represents the linear regression of the data characterised
by the equation y = 3.776 + 0.716x (r2 = 0.866).
1
In contrast to the other groups, t ⁄ β for the 40mg
2
group was calculated from the single-dose data;
therefore, the 40mg group was not included in the
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Clin Drug Invest 2001; 21 (2)

Atrasentan Multiple-Dose Pharmacokinetics
135
receptors, is postulated to inhibit tumour growth.
Atrasentan is currently under development at
Abbott Laboratories for treatment of prostate and
other cancers. Atrasentan has been evaluated
principally in patients with hormone-refractory
prostate cancer.[15] The purpose of this study was
to evaluate the multiple-dose pharmacokinetics of
atrasentan.
Atrasentan plasma concentrations increased
approximately linearly with dose. Except for the
1mg group, atrasentan plasma concentrations
increased rapidly after single- and multiple-drug
administration, declining thereafter biexponen-
tially with a study-wide harmonic mean (pseudo-
SD) half-life of 21 (12) hours and mean (SD)
CL/F of 28 (9.8) L/h. With the 1mg group, there
was no apparent distribution phase and the ab-
sorption was slower. Except for lower than pre-
Table II. Atrasentan pharmacokinetic parameters estimated from
parametric model
Parameter and unit
a (h–1
Estimate
0.16a
1.5b
CV (%)
k
)
6
3
Vc/F (L)
Vp/F (L)
CL/F (L/h)
CLd/F (L/h)
r2
11
74
1
690
29
1
270
3
0.866
a
b
1mg group.
5 to 40mg groups.
CL/F = apparent total body clearance; CLd = apparent distribution
clearance; CV = coefficient of variation; ka = absorption rate
constant; Vc/F = apparent volume of the central compartment;
Vp/F = apparent volume of the peripheral compartment.
were estimated for the 1mg group and all other
groups. Use of two different ka values resulted in
substantial improvement of the model fits and
significant reduction of the objective function
(weighted sum of squared residuals) as well as
lower Akaike Information Criteria and Schwarz
Criteria. The model-estimated ka values were
0.16h–1 for the 1mg group and 1.5h–1 for all other
groups.
Atrasentan pharmacokinetic parameters esti-
mated in this study are in excellent agreement with
previously reported values.[11] The precisions of
the parameter estimates from ADAPT were ≤6%
for all parameters except Vc. Vc was poorly esti-
mated, with a CV of 74%. The large total apparent
volume of distribution (Vc/F + Vp/F), approxi-
mately 700L, suggests extensive tissue distribution
of atrasentan.
dicted Cmax values for the 1mg group, the Cmax
,
Cmin and AUC values increased linearly with
dose, and CL/F values were similar across the
groups, after single- and multiple-dose administra-
tion. Therefore, it can be concluded that atrasentan
pharmacokinetics are dose-independent.
There are several sources of evidence for time-
independent pharmacokinetics. First, CL/F was
similar after single- and multiple-dose administra-
tion. Secondly, the pre-dose plasma concentrations
(Cmin) on days 7, 8, 9 and 10 were similar (fig. 3)
and the dose-normalised Cmin values for days 7 and
9 were not statistically significantly different.
Thirdly, the first-dose AUC∞ and last-dose (day 9)
AUC24h values were similar (fig. 2) and not statis-
tically significantly different (excluding the 1mg
group).
A two-compartment model with linear absorp-
tion, distribution and elimination optimally
characterised the plasma concentration-time data
from all groups. There was no dose dependency in
the apparent clearance; however, some dose de-
pendency in the absorption was observed, mainly
at the 1mg group. The large volume of distribution
suggests that on average 90% of the drug in the
body is in the tissue compartment. Aprevious study
of single doses of atrasentan has shown that
Discussion
Endothelins are a family of paracrine/autocrine
peptide factors that contribute to cell proliferation
and hormone production through a G-protein-
coupled pathway.[3] Dysfunction of endothelin
regulation has been implicated in several cancers,
including prostate, ovarian and breast.[3,9,14,15]
Atrasentan, a highly selective antagonist of ETA
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Clin Drug Invest 2001; 21 (2)

136
Dutta et al.
atrasentan pharmacokinetics are linear at doses
≤23.25mg.[11] Nonlinearity in tissue distribution
was observed when a higher dose of 139.5mg was
administered. The half-maximal tissue-binding
coefficient was estimated at 300 μg/L, which is
above concentrations attained in the present study.
The binding affinity (Ki) of atrasentan for ETA
receptors has been determined to be 0.034 nmol/L
(17.4 ng/L) in the absence of protein from in vitro
receptor binding studies, and this binding is atten-
uated approximately 30-fold by plasma proteins
(data on file, Abbott Laboratories). The mean (SD)
steady-state Cmax for the 1mg group was 2.6 (1.9)
μg/L, approximately 5-fold higher than the Ki
(after accounting for presence of plasma proteins)
for ETA receptors. Therefore, complete antagonism
of ETA receptors by atrasentan might be expected
at doses of 1mg or higher.
References
1. Levin ER. Endothelins. N Engl J Med 1995; 333 (6): 356-63
2. Raffa RB, Schupsky JJ, Martinez RP, et al. Endothelin-1-
induced nociception. Life Sci 1991; 49 (11): L61-5
3. Bagnato A, Catt KJ. Endothelins as autocrine regulators of
tumor cell growth. Trends Endocrinol Metab 1998; 9 (9):
378-83
4. Opgenorth TJ. Endothelin receptor antagonism. Adv Pharmacol
(New York) 1995; 33 1-65
5. Borgeson DD, Grantham JA, Williamson EE, et al. Chronic oral
endothelin type A receptor antagonism in experimental heart
failure. Hypertension 1998; 31 (3): 766-70
6. Chen SJ, Chen YF, Opgenorth TJ, et al. The orally active non-
peptide endothelin A-receptor antagonist A-127722 prevents
and reverses hypoxia-induced pulmonary hypertension and
pulmonary vascular remodeling in Sprague-Dawley rats.
J Cardiovasc Pharmacol 1997; 29 (6): 713-25
7. McKenna CJ, Burke SE, Opgenorth TJ, et al. Selective ET(A)
receptor antagonism reduces neointimal hyperplasia in a por-
cine coronary stent model. Circulation 1998; 97 (25): 2551-6
8. Opgenorth TJ, Adler AL, Calzadilla SV, et al. Pharmacological
characterization of A-127722: an orally active and highly
potent ETA-selective receptor antagonist. J Pharmacol Exp
Ther 1996; 276 (2): 473-81
9. Rosano L, Salani D, Castro VD, et al. Inhibition of tumor
growth and angiogenesis by ABT-627, an endothelin receptor
Aantagonist, in ovarian carcinoma xenografts [abstract]. Proc
Am Assoc Cancer Res 2000; 41: 327
Conclusion
Atrasentan pharmacokinetics were dose- and
time-independent after single- and multiple-dose
administration over the range of 1 to 30 mg/day.
The study-wide harmonic mean (pseudo-SD) half-
life was 21 (12) hours and mean (SD) CL/F was 28
(9.8) L/h. Steady state was achieved within 4 days
of once-daily drug administration. Atrasentan
plasma concentration-time data were optimally
characterised by a two-compartment model with
linear absorption, distribution and elimination.
Oral doses of atrasentan ranging from 1 to 30mg in
man achieve plasma concentrations that have
demonstrated biological activity in preclinical
models. This dose range will be sufficient to test
the therapeutic responses of a number of disease
states to selective and potent ETA receptor ant-
agonism.
10. Bryan PD, Sapochak LB, Tames MM, et al. Determination of
atrasentan by high performance liquid chromatography with
fluorescence detection in human plasma. Submitted for pub-
lication
11. Samara E, Dutta S, Cao G, et al. Single dose pharmacokinetics
of atrasentan, an endothelin-A receptor antagonist. J Clin
Pharmacol. In press
12. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York:
Marcel Dekker. 1982
13. D’Argenio DZ, Schumitzky A. A program package for simula-
tion and parameter estimation in pharmacokinetic systems.
Comput Programs Biomed 1979; 9 (2): 115-34
14. Ryan CW, Janus TJ, Vogelzang NJ, et al. Aphase I study of men
and women with refractory malignancies given daily dosing
of an endothelin receptor antagonist [abstract]. Proc Am Soc
Clin Oncol 2000; 19: 201a
15. Carducci MA, Vogelzang NJ, Daliani D, et al. A placebo con-
trolled phase II dose-ranging evaluation of an endothelin-A
receptor antagonist for men with hormone refractory prostate
cancer and disease-related pain [abstract]. Proc Am Soc Clin
Oncol 2000; 19: 334a
Acknowledgements
Correspondence and offprints: Dr Sandeep Dutta, Depart-
ment 4PK, Building AP13A, 100 Abbott Park Road, Abbott
Park, IL 60064-6104, USA.
Abbott Laboratories, Abbott Park, Illinois, USA, funded
this study. E. Samara is currently at Chiron Corporation, San
Francisco, CA, USA.
E-mail: Sandeep.Dutta@Abbott.com
© Adis International Limited. All rights reserved.
Clin Drug Invest 2001; 21 (2)