Full text of DOI:10.2165/00044011-200222080-00003

Clin Drug Invest 2002; 22 (8): 513-522
1173-2563/02/0008-0513/$25.00/0
ORIGINAL RESEARCH ARTICLE
© Adis International Limited. All rights reserved.
Pharmacokinetics of Gepirone in Subjects
with Normal Renal Function and in
Patients with Chronic Renal Dysfunction
Peter Dogterom,1 Jan A.M. Huisman,2 Ryszard Gellert3 and Aalt Verhagen4
1
2
3
4
Department of Clinical Pharmacology, NV Organon, Oss, The Netherlands
Department of Drug Metabolism and Kinetics, NV Organon, Oss, The Netherlands
Avoxova Sp.zo.o., Warsaw, Poland
InteGen Switzerland GmbH, Basle, Switzerland
Objective: To compare the pharmacokinetic profiles of gepirone and its main
metabolites, 1-(2-pyrimidinyl)-piperazine (1-PP) and the 3′-hydroxy derivative
(3′-OH-gepirone) after a single oral dose of gepirone extended-release (gepirone-
ER) in subjects with normal renal function and in patients with various levels of
renal dysfunction.
Abstract
Design: Open-label, parallel-group, single oral dose pharmacokinetic study.
Participants: 37 subjects, aged 35 to 65 years with normal renal function
(n = 9) or mild (n = 9), moderate (n = 9) or severe (n = 10) renal impairment
Methods: All subjects received a single oral dose of gepirone-ER (two 20mg
tablets) under fasting conditions. Participants were matched with regard to age
and body mass index. Serial blood samples were drawn over 96 hours to measure
plasma concentrations of gepirone, 1-PP and 3′-OH-gepirone. Urine was
collected to assess the excretion of gepirone and its metabolites.
Results: The exposure [area under the plasma concentration-time curve (AUC),
maximum plasma concentration (Cmax)] to gepirone, 1-PP and 3′-OH-gepirone
increased with decreasing renal function. The AUC of gepirone and its metabo-
lites was greatest in patients with the severest renal dysfunction. No difference
1
was observed in the elimination half-life (t ⁄ ) of gepirone, but the t1/2 of the
2
metabolites was longer in patients with severe dysfunction than in those with
normal renal function. Renal clearance of gepirone, 1-PP and 3′-OH-gepirone
was higher in those with normal function than in patients with severe dysfunction.
Adverse events (18) occurred more frequently only in subjects with severe renal
impairment.
Conclusions: Gepirone-ER was generally well tolerated among patients with
varying degrees of renal impairment. Exposure to gepirone and its metabolites
was increased by renal impairment, especially in subjects with severe dysfunc-
tion. Therefore, caution should be used when selecting the dose of gepirone in
patients with severe renal impairment.

514
Dogterom et al.
Gepirone is an antidepressant drug belonging to
of 1-PP was approximately 6 hours. Studies in
animal models indicate that 1-PP may be an
anxiolytic, but it is not active in animal models of
depression, although 3′-OH-gepirone is (Organon,
data on file). 3′-OH-gepirone is an agonist of 5-
HT1A receptors. Human pharmacokinetic data
were not available at the time of the study.
An extended-release formulation of gepirone
(gepirone-ER) has been developed to reduce peak-
to-trough fluctuations in plasma concentrations,
which should permit administration of higher
doses without increasing adverse effects. The
apparent t1/2 of gepirone-ER after administration
of an extended-release tablet has been observed at
4.4 hours to more than 10 hours, probably due to
extended gepirone absorption. The present study
was designed to evaluate the effect of renal insuf-
ficiency on the pharmacokinetics and tolerability
of gepirone and its main metabolites after a single
40mg oral dose of gepirone-ER.
the azapirone class of compounds. It is also char-
acterised by anxiolytic activity, based on findings
in animal models (Organon, data on file). Gepirone
acts as an agonist at the serotonin 5-HT1A receptor
and has the ability to downregulate 5-HT2 re-
ceptors.[1,2] It is predominantly eliminated by bio-
transformation. The main metabolites in plasma
are 1-(2-pyrimidinyl)-piperazine (1-PP) and the 3′-
hydroxy derivative (3′-OH-gepirone). Biotransfor-
mation of gepirone to 1-PP, 3′-OH gepirone and to
other metabolites was shown in human liver
microsomes to be mediated mainly by cytochrome
P450-3A4 (CYP3A4).[3] Cytochrome P450-2D6
(CYP2D6) is also involved in the metabolism of
gepirone to 3′-OH-gepirone and other hydroxy
metabolites, but not to 1-PP.[3]
The apparent elimination half-life (t1/2) of
gepirone after administration of an immediate-
release tablet or after intravenous administration
was reported to be approximately 3 hours.[4,5] Ap-
proximately 70% of gepirone in plasma is bound
to proteins, and the apparent volume of distribution
is 310L. Gepirone is a drug that exhibits high
hepatic extraction. The hepatic clearance is in-
dependent of liver blood flow, and the absolute
bioavailability was found to be approximately
15%. A comparison of the urinary excretion of
total 14C-radioactivity after intravenous and oral
administration of 14C-labelled gepirone showed
that gepirone, and its presystemically formed
metabolites, are completely absorbed after oral
administration (Organon, data on file). Food
increased the bioavailability of gepirone and
decreased the rate of absorption.[5] No gender
difference in its pharmacokinetics was observed
(Organon, data on file).
Methods
Subject Selection
Study participants were selected from the re-
cords of Avoxova in Warsaw, Poland. Male and
female Caucasian subjects aged 35 to 65 years with
normal or impaired renal function were eligible if
they had a body mass index (BMI) of 20 to <30
kg/m2. Thirty-seven patients and healthy volun-
teers were enrolled in the trial and 36 completed
the study. Those eligible were allocated to four
groups of nine subjects each on the basis of pre-
defined glomerular filtration rate criteria (GFR):
normal renal function, ≥82.0 ml/min/1.73m2; mild
renal insufficiency, ≥52.0 to ≤78.0 ml/min/1.73m2;
moderate renal insufficiency, ≥32.0 to ≤48.0
ml/min/1.73m2; and severe renal insufficiency,
≤28.0 ml/min/1.73m2.
The concentrations of 1-PP were in the same
range as those of the parent drug after oral ad-
ministration of gepirone, but close to or below the
limit of quantification after intravenous adminis-
tration.[6] These findings suggest that, after oral
administration of gepirone, 1-PP is predominantly
generated prehepatically, most likely in the small
bowel, where CYP3A4 is also present.[7] The t1/2
Participants showing clinically relevant devia-
tions from normal (unrelated to underlying renal
diseases) on physical examination, in clinical
laboratory tests or by electrocardiogram (ECG)
were not enrolled. Systolic and diastolic blood
pressures, respectively, were <150mm Hg and
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Clin Drug Invest 2002; 22 (8)

Gepirone Pharmacokinetics in Renal Dysfunction
515
<95mm Hg in subjects with normal renal function,
and <180mm Hg and <110mm Hg in patients with
renal dysfunction. None of the participants had
clinically relevant cardiovascular diseases (e.g.
myocardial infarction within 6 months prior to the
prestudy screening) or unstable angina pectoris.
Patients undergoing haemodialysis or having a
functioning graft were not included. Any previous
surgery of the gastrointestinal tract, except for
appendectomy, was an exclusion criterion. During
the study, the treatment regimen for any under-
lying medical condition was not changed, and no
agent known to inhibit or induce drug-metabo-
lising enzymes was allowed within 1 month before
gepirone administration.
Women were neither pregnant nor lactating. All
participants were negative in HIV and hepatitis B
and C serology, and none had a history or a current
episode of abuse of drugs or alcohol. All partici-
pants were normal metabolisers with regard to
CYP2D6 genotyping, apart from one subject with
severe renal dysfunction who was a fast metabo-
liser, and two patients, one with mild and one with
severe renal dysfunction, who were both poor
metabolisers.
urement from the middle of this 24-hour period.
In addition, at the prestudy screening and again on
the day before gepirone administration (day –1),
the serum creatinine measurement was used to es-
timate CLCR according to the method of Cockcroft
and Gault.[8] If the estimate on day –1 was within
80 to 120% of the estimate at the prestudy screen-
ing, CLCR was considered to be stable and the sub-
ject was included in the study.
Participants were allocated to four groups of
equal size according to their CLCR as assessed from
urinary and serum creatinine at the prestudy
screening. Subjects with normal renal function
(CLCR >88 ml/min/1.73m2) were put into group A,
patients with mild (CLCR 48 to 77 ml/min/1.73m2),
moderate (CLCR 32 to 47 ml/min/1.73m2), or severe
(CLCR 8.9 to 30 ml/min/1.73m2) renal dysfunction
were put into groups B, C and D, respectively.
Selection of participants was stratified to match
groups with regard to age and body mass index.
Participants were admitted to the clinical centre
on day –1 and were hospitalised for another 4 days
after gepirone administration. On study day 1,
gepirone-ER was administered under fasting con-
ditions (following an overnight fast of 10 hours) as
a single dose of 40mg, consisting of two gepirone-
ER 20mg tablets. Fasting continued until 4 hours
after gepirone administration. Food and drinks
containing xanthine derivatives, like coffee, tea,
cocoa or grapefruit, were not allowed from 24
hours before gepirone administration until after
the post-study examination.
Blood samples of 6ml were collected into K-
EDTA tubes immediately before (predose) and at
0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 30, 36, 48, 60, 72
and 96 hours after gepirone administration to
determine plasma concentrations of gepirone, 1-
PP and 3′-OH-gepirone. Urine was collected be-
fore gepirone administration (blank sample) and
quantitatively in two 24-hour intervals until 48
hours after gepirone administration. Plasma sam-
ples and aliquots of the urine portions were stored
at –200C until analysed. Measurements of vital
signs (blood pressure, pulse rate) further to those
at the prestudy screening and at the post-study
Study Design
Within 3 weeks before study drug administra-
tion (day 1), participants underwent a prestudy
screening to examine their eligibility for study
entry. The screening included a medical history,
physical examination, measurement of vital signs
(blood pressure, pulse rate), clinical laboratory
tests (haematology, serum biochemistry, urinaly-
sis, drug screen and serology), and a 12-lead ECG.
The same assessments as at the prestudy screening
(except for recording of the medical history, drug
screen and serology) were performed at the time of
a post-study examination, which took place 5 days
after gepirone administration.
At the prestudy screening, potential participants
were hospitalised for 24 hours and a 24-hour urine
specimen was obtained. Creatinine clearance
(CLCR) was calculated from the 24-hour urinary
creatinine excretion and a serum creatinine meas-
© Adis International Limited. All rights reserved.
Clin Drug Invest 2002; 22 (8)

516
Dogterom et al.
examination were taken on day –1 and in the morn-
ing (before blood sampling) of days 1 through 5.
into urine in the interval 0 to 24 hours and the cor-
responding plasma AUC over 24 hours. Although
urinary excretion was measured over 48 hours,
CLR was estimated from 24-hour urine because
in each subject the concentrations of all three
compounds were measurable at 24 hours and no
extrapolation was necessary to calculate the corre-
sponding AUC. CLR was standardised to a body
surface area of 1.73m2. The cumulative amount
excreted in urine over 48 hours (U48h) was calcu-
lated by multiplying the urine volumes with the
corresponding concentrations in urine.
Analytical Methods
Concentrations of gepirone, 1-PP and 3′-OH-
gepirone in plasma were measured by electrospray
liquid chromatography/mass spectrometry (LC/MS)
methods, using buspirone (gepirone, 3′-OH-
gepirone) or 2-aminonorbornane (1-PP) as internal
standards (Organon, data on file). The method was
validated with a lower limit of quantification of
0.025 μg/L for gepirone, 0.2 μg/L for 1-PP, and
0.25 μg/L for 3′-OH-gepirone. The accuracy and
precision met internationally accepted guide-
lines.[9] For gepirone, the accuracy at concentra-
tions of 0.30, 4.00 and 8.00 μg/L, respectively, was
100, 104 and 103%, and the interassay precision
was 17.9, 9.30 and 7.66%. For 1-PP the accuracy
at concentrations of 0.60, 4.00 and 8.00 μg/L,
respectively, was 104, 96.8 and 95.7%, and the
interassay precision was 16.5, 13.0 and 13.0%. For
3′-OH-gepirone, the accuracy at concentrations of
0.30, 4.00 and 8.00 μg/L, respectively, was 109,
101 and 103%, and the interassay precision was
19.3, 11.5 and 10.1%. Gepirone, 1-PP and 3′-OH-
gepirone in urine were analysed using electrospray
LC/MS methods, similar to those for the analysis
in plasma. The accuracy and precision of the deter-
minations in urine also met accepted guidelines.[9]
Statistical Analysis
Arithmetic means and corresponding standard
1
deviations (SD) were calculated for tmax, t ⁄ , CLCR
2
and CLR, and geometric means for Cmax, AUC0-∞
,
and U48h. The log-transformed parameters Cmax
,
AUC0-∞ , t1/2 and CLR were subjected to an analysis
of variance (ANOVA) with the factor group (pro-
cedure GLM, SAS® version 6.12). If the ANOVA
indicated a significance (p < 0.05), a pairwise com-
parison of groups was done using the Bonferroni
test. The tmax of gepirone was compared among
groups using the nonparametric Kruskal-Wallis
test. The Pearson correlation coefficient was used
to assess a possibly linear relationship between
CLCR and CLR of the compounds concerned. Data
on tolerability (vital signs, ECG, laboratory tests,
physical examination parameters, adverse events)
were evaluated descriptively, in terms of rates or
by descriptive statistics, where appropriate.
Pharmacokinetic Evaluation
The maximum plasma concentration (Cmax) and
the time to reach Cmax (tmax) of gepirone, 1-PP and
3′-OH-gepirone were taken directly from the
plasma concentration versus time curves. The t1/2
was estimated by log-linear regression of concen-
tration versus time data in the terminal phase of the
plasma concentration versus time curves. The area
under the concentration versus time curve until
time infinity (AUC0-∞) was estimated by the linear
trapezoidal rule until the timepoint of the last
measured (or measurable) plasma concentration,
followed by extrapolation to time infinity using
t1/2. Renal clearances (CLR) of the three com-
pounds were derived from the amounts excreted
Results
In total, 36 participants were evaluable for
pharmacokinetic determinations in plasma and
urine. One patient with severe renal dysfunction
vomited 1 hour after gepirone administration. This
subject was withdrawn from the study and replaced
by another patient with the same degree of renal
dysfunction. Thus, 37 participants were included
in the evaluation of tolerability.
A summary of the demographic characteristics
of the participants is given in table I. The partici-
pants had a body mass index between 20.0 and 29.4
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Clin Drug Invest 2002; 22 (8)

Gepirone Pharmacokinetics in Renal Dysfunction
517
Table I. Summary (mean SD) of demographic characteristics of the study participants
Parameter
Group A
9
Group B
9
Group C
9
Group D
9
n
Degree of renal impairment
Creatinine clearance (ml/min/1.73m2)
Male/female (no.)
Age (y)
None
Mild
Moderate
32-47
Severe
>88
48-77
8.9-30
8/1
8/1
9/0
4/5
43.9 5.51
78.4 5.79
1.75 0.06
25.7 2.31
97.4 5.33
126 13
80.6 7.5
73.0 15
47.2 10.4
80.8 10.2
1.73 0.08
27.0 2.70
62.9 12.7
150 17
87.3 9.8
78.0 10
50.9 8.01
78.9 6.65
1.74 0.03
26.0 1.99
39.7 5.01
150 18.4
96.8 8.9
73.8 21
45.6 6.82
75.6 14.4
1.70 0.10
26.1 2.97
16.9 6.17
138 16
83.8 11
72.0 11
Bodyweight (kg)
Height (m)
BMI (kg/m2)
CLCR (ml/min/1.73m2)
Systolic BP (mm Hg)a
Diastolic BP (mm Hg)a
Pulse rate (beats/min)a
a
BP and pulse rate were measured on day –1.
BMI = body mass index; BP = blood pressure; CLCR = creatinine clearance standardised to a body surface area of 1.73m2.
kg/m2. Mean SD CLCR (ml/min/1.73m2) was
97.4 5.3, 62.9 12.7, 39.7 5.0 and 16.9 6.2
in groups A through D, respectively. Participants
in the different groups were well matched with
regard to age and body mass index. Considerably
more males than females were included in groups
A, B and C, whereas more females were included
in group D.
23 ml/min/1.73m2) in group D (p = 0.059). The
ANOVA did not indicate a significant difference
among groups in the excretion of gepirone in urine
(p = 0.25). The Pearson correlation coefficient
between CLCR and CLR was 0.33 (p = 0.0476).
Overall, the pharmacokinetic parameters of
gepirone showed a high interindividual variability.
Plasma concentrations of 1-PP rose with in-
creasing renal dysfunction (figure 1). AUC0-∞
increased significantly (p = 0.0054), and AUC0-∞
in group D was significantly larger than that in
group A. Cmax showed a similar increase (p = 0.024),
and in group D, Cmax was significantly higher than
that in group A. The t1/2 of 1-PP in group D was
significantly longer (p = 0.0002) than that in group
A. The CLR of 1-PP significantly decreased with
increasing renal dysfunction (p < 0.001). The mean
CLR in group A was 94 ml/min/1.73m2 (range 48
to 155 ml/min/1.73m2) and declined to 25
ml/min/1.73m2 (range 15 to 44 ml/min/1.73m2) in
group D (table II). The differences were significant
(p = 0.001) between group A and group D, respec-
tively. The difference among groups in the urinary
excretion of 1-PP was not significant (p = 0.86).
The Pearson correlation coefficient between CLCR
and CLR was 0.42 (p = 0.01).
Pharmacokinetics
Descriptive statistics of pharmacokinetic para-
meters are presented in table II. In parallel with the
steady increase in plasma concentrations of gepi-
rone with increasing renal dysfunction (figure 2),
the AUC0-∞ tended to increase (p = 0.072). The
mean AUC0-∞ in group D was 70% larger than that
in group A. Furthermore, Cmax tended to increase
(p = 0.094) with increasing renal dysfunction, and
the mean Cmax in group D was nearly twice as high
as that in group A. No significant difference among
1
groups (p = 0.84) was observed in the t ⁄ of
2
gepirone. The median tmax was between 4.0 and 5.0
hours, without any evidence of a difference among
groups (Kruskal-Wallis test, p = 0.45).
The mean CLR of gepirone in group A was
31 ml/min/1.73m2 (range 14 to 61 ml/min/1.73m2)
and remained essentially unchanged in groups B
(29 ml/min/1.73m2) and C (29 ml/min/1.73m2),
but declined to 12 ml/min/1.73m2 (range 5.9 to
The concentrations of 3′-OH-gepirone in
plasma (figure 3) and the corresponding AUC0-∞
rose significantly with increasing renal dys-
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Clin Drug Invest 2002; 22 (8)

518
Dogterom et al.
Table II. Summary (mean SD)a of pharmacokinetic parameters of gepirone, 1-(2-pyrimidinyl)-piperazine (1-PP), and the 3′-hydroxy
derivative (3′-OH-gepirone)
Parameters
Group A
9
Group B
9
Group C
9
Group D
9
n
Degree of renal impairment
Creatinine clearance (ml/min/1.73m2)
None
>88
Mild
Moderate
32-47
Severe
8.9-30
48-77
Gepirone
t
max (h)
5.0 1.8
7.60 2.49
6.0 3.7
107 42.5
31 16
4.7 2.6
9.73 4.36
6.1 3.7
147 59
29 22
4.0 1.7
12.4 6.98
4.6 1.6
182 82.4
29 15
3.8 1.8
14.2 7.02
6.2 4.1
194 100
12 5.9
C
max (μg/L)
t1/2 (h)
AUC0-∞ (μg•h/L)
CLR b (ml/min/1.73m2
U48h c (μg)
)
203 143
232 195
292 240
149 121
1-PP
tmax (h)
5.0 0.9
5.84 2.28
7.2 2.7
97.5 53.7
94 42
9.0 8.4
5.93 2.77
8.1 2.3
144 123
56 36
7.7 2.8
7.65 3.10
7.3 3.11
169 121
49 21
14 8.8
C
max ( μg/L)
11..1 6.07
16 8.2
t1/2 (h)
AUC0-∞ (μg•h/L)
CLR (ml/min/1.73m2)
335 210
25 9.4
U
48h (μg)
457 466
336 516
457 464
444 344
3-OH-gepirone
max (h)
t
5.4 1.1
13.3 5.79
7.0 2.2
256 103
43 13
5.6 1.0
15.7 8.89
8.6 2.1
331 139
34 22
9.0 6.1
15.6 2.94
10 4.9
9.6 8.2
21.2 11.2
12 3.0
C
max (μg/L)
1
t ⁄2 (h)
AUC0-∞ (μg•h/L)
CLR (ml/min/1.73m2)
U48h (μg)
367 81.6
28 12
591 248
12 5.6
715 275
665 416
642 413
388 244
a
b
c
Arithmetic mean and corresponding SD for tmax, t1/2, and CLR for Cmax, AUC0-∞, and U48h.
Calculated from excretion in 24-hour urine, standardised to a body surface area of 1.73m2.
Cumulative amount excreted over 48 hours.
AUC0-∞ = area under the concentration versus time curve until time infinity; CLR = renal clearance; Cmax = maximum plasma concentration;
1
t
2 = apparent elimination half-life; tmax = time to reach Cmax ; U48h = cumulative amount excreted in urine over 48 hours.
⁄
function (p = 0.0033). In group D, AUC0-∞ was
significantly (p = 0.0004) larger than in group A.
However, no significant difference was observed
among groups in Cmax (p = 0.22). The ANOVA
and the Bonferroni test revealed a significant
(p = 0.0003) prolongation in t1/2 of 3′-OH-gepirone
in group D compared with group A. The mean
CLR of 3′-OH-gepirone in group A was 43
ml/min/1.73m2 (range 26 to 67 ml/min/1.73m2) and
decreased to 12 ml/min/1.73m2 (range 4 to 19
ml/min/1.73m2) in group D. The differences were
significant (p < 0.001) between group D and
groups A and B, respectively. The urinary excre-
tion of 3′-OH-gepirone in group D was lower than
that in the other groups (p = 0.082). The Pearson
correlation coefficient between CLCR and CLR was
0.47 (p = 0.0038).
Tolerability
Eighteen (49%) of the 37 subjects experienced
at least one adverse event, including four (44%)
subjects with normal renal function, three (33%)
subjects with mild impairment, two (22%)
patients with moderate impairment, and nine
(90%) subjects with severe impairment (table III).
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Clin Drug Invest 2002; 22 (8)

Gepirone Pharmacokinetics in Renal Dysfunction
519
among subjects with varying degrees of renal im-
pairment.
Normal renal function
Mild dysfunction
Moderate dysfunction
Severe dysfunction
12
10
8
No clinically relevant changes in physical ex-
amination, laboratory parameters, ECG para-
meters or the medical condition of any subject
were recorded, taking into account the underlying
disease of the patients. Similarly, vital sign meas-
urements revealed that gepirone-ER did not affect
systolic or diastolic blood pressure or pulse rate in
subjects with either normal renal function or vari-
ous levels of renal dysfunction.
6
4
2
0
0
4
8
12
16
20
24
28
32
36
Time (h)
Discussion
Fig. 1. Mean plasma concentrations of gepirone in subjects with
normal renal function, mild dysfunction, moderate dysfunction
or severe renal dysfunction.
The present study showed that the elimination
of gepirone and its metabolites is affected by renal
impairment. Previous studies indicated that the
renal clearance of gepirone accounts for only 4%
of the total clearance of this drug (Organon, data
on file). The t1/2 of gepirone observed in healthy
subjects in the present study was in the same range
(approximately 6 hours) as that observed in
previous studies (Organon, data on file) of the
extended-release formulation of gepirone. The
longer half-life, compared with administration in
an immediate-release tablet (3 hours), was ex-
plained by a continued absorption of gepirone af-
ter extended release. As shown in figure 1, plasma
concentrations of gepirone rose with progressive
Normal renal function
Mild dysfunction
Moderate dysfunction
Severe dysfunction
10
9
8
7
6
5
4
3
2
1
0
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60
Time (h)
Fig. 2. Mean plasma concentrations of 1-PP in subjects with
normal renal function, mild dysfunction, moderate dysfunction
or severe renal dysfunction.
20
18
16
14
12
10
8
Normal renal function
Mild dysfunction
Moderate dysfunction
Severe dysfunction
No serious adverse events were observed. In total,
29 adverse events were reported, the most common
being headache (10 events), dizziness (eight
events), somnolence (seven events), nausea (two
events), and vomiting (two events). One patient
with severe renal impairment had severe dizziness,
nausea and vomiting 1 hour after administration
and was withdrawn from the study. The other
adverse events in this study were either moderate
(17 events) or mild (nine events), demonstrating
that gepirone-ER was generally well tolerated
6
4
2
0
0
6
12 18 24 30 36 42 48 54 60
Time (h)
Fig. 3. Mean plasma concentrations of 3′-OH-gepirone in
subjects with normal renal function, mild dysfunction, moderate
dysfunction or severe renal dysfunction.
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Clin Drug Invest 2002; 22 (8)

520
Dogterom et al.
Table III. Summary of adverse events
Adverse event
No. (%) of events
normal renal function
(n = 9)
mild impairment
(n = 9)
moderate impairment
(n = 9)
severe impairment
(n = 10)
9 (90)
4 (40)
5 (50)
2 (20)
1 (10)
6 (60)
No. of subjects with ≥1 event
Headache
4 (44)
3 (33)
1 (11)
0
3 (33)
1 (11)
1 (11)
0
2 (22)
2 (22)
1 (11)
0
Dizziness
Nausea
Vomiting
0
0
1 (11)
0
Somnolence
0
1 (11)
renal dysfunction, resulting in a trend towards
increased AUC0-∞ and Cmax values. The present
data in healthy subjects fit very well with pharma-
cokinetic data from healthy individuals from other
studies of gepirone (Organon, data on file).
intrinsic hepatic clearance (enzyme activity/capac-
ity). Thus, a change in the intrinsic hepatic clear-
ance has no effect on the t1/2 of gepirone. AUC0-∞
is a direct function of intrinsic hepatic clearance;
therefore, it is reasonable to conclude that the
increase in AUC0-∞ of gepirone with increasing
degrees of renal impairment results from a de-
crease in the intrinsic hepatic clearance, which
may accompany severe renal disease.
Biotransformation of gepirone to 1-PP and to
other metabolites is mediated mainly by
CYP3A4.[3] CYP3A4 is also present in the small
bowel,[7] and small bowel and hepatic CYP3A4
appear to be regulated independently.[8] Therefore,
an increase in intestinal absorption of gepirone as
a consequence of a decrease in CYP3A4 activity
in the small bowel cannot be excluded.
An explanation of the increased AUC (and
C
max) values of gepirone with increasing renal dys-
function is not immediately evident. The CLR of
gepirone accounts for less than 4% of total clear-
ance. A decrease in CLR by a factor of 4 then leads
to an increase in AUC0-∞ of 3%. The AUC0-∞ of
gepirone can be described by the following equa-
tions:
AUC0-∞
F =
=
FD
[Eq. 1]
[Eq.
(CLH + CLR)
Q
The AUC0-∞ of a metabolite is dependent, in a
complicated way, on several factors. AUC0-∞ can
be described by the following equation:
2]
(Q + CLi)
where FD is the fraction of the dose of gepirone
that escaped the prehepatic first-pass metabolism,
CLH and CLR are the hepatic and renal clearance,
respectively, Q is the hepatic blood flow and CLi
is the intrinsic hepatic clearance of gepirone.
The relatively weak binding of gepirone to
plasma proteins (70%) also leaves changes in bind-
ing as an unlikely explanation for the change in
AUC0-∞, in particular with regard to the unaltered
half-life of elimination.
AUC0-∞ = [f CLH(p) AUC0-∞(p) + Aint + Ahep] [Eq. 3]
(CL H + CLR)
where f is the fraction of the parent drug converted
to the corresponding metabolite, CLH(p) and
AUC0-∞(p) are the hepatic clearance and AUC0-∞, re-
spectively, of the parent compound gepirone. Aint is
the amount of the metabolite formed prehepatically
(intestine)andreaching the systemic circulation, Ahep
is the amount formed during hepatic first-pass of
gepirone and CLH and CLR are the hepatic and renal
clearance, respectively, of the metabolite.
Gepirone is characterised by a high extraction
ratio. As a result, its systemic clearance is deter-
mined by liver blood flow, but is independent of
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Clin Drug Invest 2002; 22 (8)

Gepirone Pharmacokinetics in Renal Dysfunction
521
The AUC0-∞ of a metabolite may depend on sys-
temic formation from gepirone (essentially deter-
mined by liver blood flow), the amount formed
during hepatic first-pass elimination of gepirone
(intrinsic clearance of gepirone), the amount
formed during the prehepatic first-pass metabo-
lism of gepirone (intestine), the systemic hepatic
clearance, and the renal clearance. The hepatic
first-pass elimination of the metabolite very likely
represents another contributory factor. The data do
not allow differentiation of these processes, but the
complex dependencies may explain why no direct
relationship exists between the exposure to the
metabolites and the degree of renal dysfunction.
Generally, the pharmacokinetics of antidepres-
sants in renal impairment are complex and heavily
impacted by the presence of metabolites.[10]
Following oral administration of 14C-labelled
gepirone in a solution, 81% of 14C-activity was
recovered in urine over 6 days (Organon, data on
file). In the present study, the sum of the amounts
of gepirone, 1-PP and 3′-OH-gepirone excreted
over 48 hours in urine accounted for less than 4%
of the dose of gepirone (table II).
parameters did not show clinically relevant
changes in any group.
Conclusion
The exposure to gepirone, 1-PP and 3′-OH-
gepirone increased to various degrees with pro-
gressive renal dysfunction. Patients with severe
renal dysfunction showed the greatest increase. No
difference was seen among the groups in the half-
life of elimination of gepirone, but the half-lives
of 1-PP and 3′-OH-gepirone were significantly
longer in patients with severe dysfunction than in
healthy subjects. The renal clearance of gepirone,
1-PP and 3′-OH-gepirone, respectively, declined
with increasing renal dysfunction. The rate of
adverse events was elevated in patients with severe
renal dysfunction, most likely related to the in-
creased and prolonged exposure to the metabolites
of gepirone. Caution should be used when select-
ing the dose of gepirone in patients with severe
renal impairment.
A single oral dose of gepirone-ER in subjects
with normal renal function or with different
degrees of renal dysfunction was in general well
tolerated. The pattern of adverse events in the pres-
ent study was in line with the pattern observed in
previous single- and multiple-dose studies (Orga-
non, data on file), in which dizziness (lightheaded-
ness), headache, nausea and somnolence were the
most common adverse events. In the present study,
only patients with severe renal dysfunction expe-
rienced a considerably higher number of adverse
events (18), in particular headache, dizziness and
somnolence, compared with subjects with normal
function or less severe dysfunction (three to four
adverse events/group). The higher rate of adverse
events in those with severe dysfunction may have
been related to their medical condition, but could
Acknowledgements
This study was sponsored by NV Organon, Oss, The
Netherlands. The determination of gepirone, 1-PP and 3′-
OH-gepirone in plasma and urine was performed at TexMS
Inc., Houston, Texas, USA.
References
1. Eison AS, Eison MS, Stanley M, et al. Serotonergic mecha-
nisms in the behavioral effects of buspirone and gepirone.
Pharmacol Biochem Behav 1986; 24: 701-7
2. De Vry JM, Schreiber T, Glaser T, et al. Behavioral pharma-
cology of 5-HT1A agonists: animal models of anxiety and
depression. In: Stahl SM, Gastpar M, Keppel Hesselink JM,
Traber J, editors. Serotonin 1A receptors. New York: Raven
Press, 1992: 55-81
3. Von Moltke LL, Greenblatt DJ, Grassi JM, et al. Gepirone and
1-(2-pyrimidinyl)-piperazine in vitro: human cytochromes
mediating transformation and cytochrome inhibitory effects.
Psychopharmacol 1998; 140: 293-9
also be a consequence of the increased (AUC0-∞
)
and prolonged (t1/2) exposure to the metabolites of
gepirone. Clinical laboratory parameters, vital
signs, ECG recordings or physical examination
4. Tay LK, Dixon JF, Sostrin MB, et al. The site of gastrointestinal
absorption of gepirone in humans. J Clin Pharmacol 1992; 32:
827-32
© Adis International Limited. All rights reserved.
Clin Drug Invest 2002; 22 (8)

522
Dogterom et al.
5. Tay LK, Sciacca MA, Sostrin MB, et al. Effect of food on the
9. Conference Report. Analytical methods validation: bioavaila-
bility, bioequivalence and pharmacokinetic studies. J Pharm
Sci 1992; 81: 309-12
bioavailability of gepirone in humans. J Clin Pharmacol 1993;
33: 631-5
6. Tay LK, Farmen RH, Pittman KA. Pharmacokinetics (PK) and
disposition of gepirone (GE) and 1-pyrimidinylpiperazine (1-
PP) in humans after intravenous (i.v.) and oral (p.o.) admin-
istration of LC-gepirone [abstract]. Pharm Res 1990; 7: S208
7. Watkins PB, Wrighton SA, Schuetz EG, et al. Identification of
glucocorticoid-inducible cytochromes P-450 in the intestinal
mucosa in rats in man. J Clin Invest 1987; 80: 1029-39
8. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharma-
codynamic consequences and clinical relevance of cyto-
chrome P450 3A4 inhibition. Clin Pharmacokinet 2000; 38:
41-57
10. Bengtsson F, Hoglund P, Timmer C, et al. Mirtazapine oral
single dose kinetics in patients with different degrees of renal
failure. Hum Psychopharmacol 1998; 13: 357-65
Correspondence and offprints: Dr Peter Dogterom, Clinical
Pharmacology Department, NV Organon, PO Box 20, 5340
BH Oss, The Netherlands.
E-mail: peter.dogterom@organon.com
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Clin Drug Invest 2002; 22 (8)