DRUG INTERACTIONS
ARTICLE
CITROME
10.1177/0091270004269870
ARIPIPRAZOLE
DRUG INTERACTIONS
ET ALAND CONCOMITANT LITHIUM AND VALPROATE
Pharmacokinetics of Aripiprazole and
Concomitant Lithium and Valproate
Leslie Citrome, MD, MPH, Richard Josiassen, PhD, Nigel Bark, MD,
Daniel E. Salazar, PhD, and Suresh Mallikaarjun, PhD
The objective of this study was to assess the pharmacokinetics
of the antipsychotic aripiprazole when coadministered with
lithium or valproate. Two open-label, sequential treatment de-
sign studies were conducted in chronically institutionalized pa-
tients with schizophrenia or schizoaffective disorder requir-
ing treatment with lithium (n = 12) or valproate (divalproex
sodium) (n = 10). Patients received aripiprazole 30 mg/day on
days 1 to 14 and aripiprazole with concomitant therapy on
days 15 to 36. Lithium was titrated from 900 mg until serum
concentrations reached 1.0 to 1.4 mEq/L for at least 5 days.
Valproate was titrated to 50 to 125 mg/L. Coadministration with
lithium increased mean Cmax and AUC values of aripiprazole by
about 19% and 15%, respectively, whereas the apparent oral
A ntipsychotics are frequently coadministered with
lithium or valproate in patients with bipolar dis-
order, schizoaffective disorder, or schizophrenia, with
coprescribing rates of antipsychotics with mood stabi-
lizers reported as high as 59%.1-3 Improved efficacy
over monotherapy with mood stabilizers has been
firmly established for bipolar mania.4-9 Combination
treatment with an antipsychotic and a mood stabilizer
From the Nathan S. Kline Institute for Psychiatric Research and the
Rockland Psychiatric Center, Orangeburg, New York, and New York Uni-
versity School of Medicine, New York (Dr Citrome); Arthur P. Noyes Re-
search Foundation, Norristown, Pennsylvania, and the University of Penn-
sylvania School of Medicine, Philadelphia, Pennsylvania (Dr Josiassen);
Bronx Psychiatric Center and the Albert Einstein College of Medicine,
Bronx, New York (Dr Bark); Bristol-Myers Squibb, Lawrenceville, New Jer-
sey (Dr Salazar); and Otsuka Maryland Research Institute, Rockville, Mary-
land (Dr Mallikaarjun). Dr Salazar is currently with Sankyo Pharma Devel-
opment, Edison, New Jersey. Bristol-Myers Squibb Company and Otsuka
Pharmaceutical Co, Ltd, sponsored this study. Adapted from a poster pre-
sented at the XXIII CINP Congress, Montreal, Canada, June 2002 (Int J
Neuropsychopharmacol 2002;5(suppl 1):S187. Submitted for publica-
tion May 19, 2004; revised version accepted August 4, 2004. Address for
reprints: Leslie Citrome, MD, MPH, 140 Old Orangeburg Road,
Orangeburg, NY 10962.
DOI: 10.1177/0091270004269870
J Clin Pharmacol 2005;45:89-93
clearance decreased by 15%. There was no effect on the
steady-state pharmacokinetics of the active metabolite of
aripiprazole. Coadministration with valproate decreased the
AUC and Cmax of aripiprazole by 24% and 26%, respectively,
with minimal effects on the active metabolite. Therapeutic
doses of lithium and divalproex had no clinically significant
effects on the pharmacokinetics of aripiprazole in patients
with schizophrenia or schizoaffective disorder.
Keywords: Aripiprazole; valproate; lithium; schizophrenia;
pharmacokinetics
Journal of Clinical Pharmacology, 2005;45:89-93
©2005 the American College of Clinical Pharmacology
may be more efficacious in schizophrenia than
antipsychotic monotherapy. 10,11 Hence, because
polypharmacy is so common in the treatment of these
complex psychiatric illnesses, it is important to evalu-
ate the pharmacokinetics of antipsychotic coadminis-
tration with lithium and valproate.
Aripiprazole is a newly developed antipsychotic
with a unique pharmacologic profile of dopamine D2
partial agonism, serotonin 5-HT1A partial agonism,
and 5-HT2A antagonism12,13 and is currently approved
by the Food and Drug Administration for the treatment
of schizophrenia.14 It is extensively metabolized by the
liver via dual metabolic pathways involving the CYP
3A4 and CYP 2D6 enzyme systems.14 Aripiprazole is
the predominant drug moiety in systemic circulation.
At steady state, dehydro-aripiprazole (OPC-14857), the
active metabolite, represents about 39% of aripiprazole
AUC in plasma. At therapeutic concentrations,
aripiprazole and its major metabolite are greater than
99% bound to serum proteins, primarily to albumin.14
We report the results from 2 studies that assessed the
pharmacokinetics of aripiprazole during coadmin-
istration of lithium15,16 or valproate17 with aripiprazole
in chronically institutionalized patients with schizo-
phrenia or schizoaffective disorder.
89
 CITROME ET AL
MATERIALS AND METHODS
Two open-label, sequential treatment design studies
were conducted at 3 state-operated psychiatric centers:
Rockland and Bronx Psychiatric Centers in New York
state and Norristown State Hospital in Pennsylvania.
The time period was April 2000 to March 2001.
Among the inclusion criteria were a DSM-IV diagno-
sis of schizophrenia or schizoaffective disorder that re-
quired lithium or valproate for the management of
symptoms, aged 18 to 55 years, and able to give in-
formed consent and/or consent obtained from a legally
acceptable representative (as required by the local in-
vestigational review boards that approved the studies).
Excluded from both studies were subjects with a his-
tory of recent (within 6 months) drug or alcohol abuse;
a diagnosis of delirium, dementia, or amnestic or other
cognitive disorders; presence of focal or epileptiform
abnormalities in screening electroencephalogram
(EEG); need for any concomitant medications that
might potentially interfere with metabolism of
aripiprazole, lithium, or valproate; positive hepatitis B
surface antigen or hepatitis C antibody test at screen-
ing; and evidence of organ dysfunction or any clini-
cally significant deviation from normal in the physi-
cal, electrocardiographic, or clinical laboratory
examinations.
The following tests and procedures were done at
baseline and at regular intervals during the trial: physi-
cal examination, vital signs, clinical laboratory, elec-
trocardiogram (ECG), EEG, Positive and Negative
Syndrome Scale (PANSS), Mini-Mental State Exam
(MMSE), Simpson-Angus Scale, Barnes Akathisia
Scale, and the Abnormal Involuntary Movement Scale.
After a medication washout period, subjects on day
1 were administered aripiprazole 30 mg once daily (2
tablets of 15 mg) for the duration of the study. On day
14, serial blood samples were collected for the determi-
nation of aripiprazole pharmacokinetics. Beginning on
day 15 and lasting for the next 21 days (days 15-36),
lithium (lithium carbonate slow-release tablets) or
valproate (divalproex sodium) was coadministered
with aripiprazole.
The lithium dose was titrated upward from a start-
ing dose of 900 mg (in a once- or twice-daily regimen)
until serum lithium concentrations approached the
upper end of the lithium therapeutic concentration
range (1.0-1.4 mEq/L) and were maintained for at least
5 days or until dose-limiting adverse events were ob-
served. For patients in the valproate study, the dose
was titrated upward from a starting dose of 250 mg
twice a day until a serum concentration of 50 to 125
mg/L was achieved or until dose-limiting adverse
90 • J Clin Pharmacol 2005;45:89-93
events were observed. After day 21, the dose of
valproate was held constant for the following 2 weeks
(days 22-36). On the final day of lithium or valproate
and aripiprazole coadministration, serial blood sam-
ples were collected for the determination of
aripiprazole pharmacokinetics in the presence of
therapeutic concentrations of lithium or valproate.
Pharmacokinetic sample collection was accom-
plished by collecting venous blood at each of the fol-
lowing time points (relative to aripiprazole administra-
tion): 0 (prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24
hours. Trough concentrations (Cmin) were determined
from the day 14 and day 36 predose samples. Pharmaco-
kinetic measures for orally administered aripiprazole
and its active metabolite, OPC-14857, were derived
from plasma concentration versus time data. The fol-
lowing pharmacokinetic parameters were determined
by study day (days 14 and 36): peak plasma concentra-
tion (Cmax), time to reach Cmax (tmax), area under the
plasma concentration-time curve over the dosing inter-
val (AUCτ), and apparent oral clearance (CLT/F). Geo-
metric means and coefficients of variation for Cmax and
AUC on days 14 and 36, as well as corresponding ratios
of day 36 values to day 14 values, were also deter-
mined. Medians and ranges were calculated for tmax.
Means, standard deviations, and ranges were calcu-
lated for Cmin and CLT/F.
Assays for aripiprazole and metabolite concentra-
tions and pharmacokinetic analyses were performed
under the supervision of the bioanalytical group of the
Clinical Discovery Department at Bristol-Myers
Squibb. Assays for lithium and valproate concentra-
tions were performed using standard commercial
methods by duly licensed laboratories.
RESULTS
The lithium study enrolled 12 subjects, with 7 com-
pleters (all male) whose results are reported here. The
average age was 37 years (range, 20-47), with 3 of white
ethnicity, 3 black, and 1 Hispanic. Mean weight was
95.3 kg (range, 66.6-143.1), mean height was 174.7 cm
(range, 167.6-188.0), and mean body mass index was
33.5 (range, 23.9-42.7). The daily dose of lithium
ranged from 1200 to 1800 mg/d. Actual lithium plasma
levels achieved ranged from 0.43 to 1.2 mEq/L.
Coadministration of lithium with aripiprazole had no
major effect on the steady-state pharmacokinetics of
aripiprazole (Table I and Figure 1). The geometric mean
Cmax and AUCτ values of aripiprazole increased by
about 19% and 15%, respectively, while the apparent
oral clearance decreased by 15%. However, there were
no consistent differences in the Cmax, AUCτ, and CLT/F
 ARIPIPRAZOLE AND CONCOMITANT LITHIUM AND VALPROATE

Table I Pharmacokinetic Parameters for Aripiprazole (ARI) and OPC-14857 (OPC)

With Lithium (Li) (n = 7) or Valproate (VAL) (n = 6)
ARI OPC ARI OPC
Parameter ARI ARI + Li ARI ARI + Li ARI ARI + VAL ARI ARI + VAL

Cmax, ng/mL, geometric mean and 364.1 431.5 115.1 136.2 426.9 315.5 109.4 101.9
coefficient of variation (%) (23) (28) (34) (25) (23) (27) (19) (30)
Median tmax, h 2.0 2.0 24.0 2.0 2.0 4.0 2.0 3.5
(minimum, maximum) (2.0, 24.0) (1.0, 12.0) (0.0, 24.0) (0.0, 24.0) (1.0, 2.0) (2.0, 24.0) (0.5, 2.0) (0.5, 24.0)
AUCτ, ng•h/mL,a geometric 6113 7041 2360 2534 7474 5677 2202 2021
mean and coefficient of (34) (18) (36) (17) (19) (25) (24) (32)
variation (%)
CLT/F, mL/min,a mean and 85.1 72.1 67.9 90.3
standard deviation (24.8) (14.1) (12.3) (22.4)
Weight-normalized CLT/F, 0.97 0.80 0.82 1.08
mL/min/kg,a mean and (0.44) (0.21) (0.18) (0.25)
standard deviation
Cmin, ng/mL, mean and 212.3 230.9 108.0 115.2 281.2 219.1 98.2 87.0
standard deviation (82.6) (72.1) (33.2) (29.4) (65.8) (97.4) (15.8) (32.8)
Treatment ratiob of Cmax and NA 1.19 NA 1.18 NA 0.74 NA 0.93
AUCτa geometric mean and (34) (21) (26) (39)
coefficient of variation (%) 1.15 1.07 0.76 0.92
(31) (25) (29) (34)
a. n = 6 for ARI and Li.
b. ARI with Li or VAL (day 36) to ARI alone (day 14).

values of aripiprazole in individual subjects adminis-

tered aripiprazole alone and aripiprazole with lithium. Aripiprazole alone Aripiprazole + Lithium
Coadministration of lithium with aripiprazole also had
Aripiprazole Concentration (ng/mL)

450
no apparent effect on the steady-state pharmaco- 400
kinetics of the major aripiprazole metabolite, dehydro- 350
aripiprazole (OPC-14857). 300
The valproate study enrolled 10 male subjects, with 250
6 completers whose results are reported here. The aver- 200
age age was 33 years (range, 22-40), with 4 of black eth- 150
nicity, 1 white, and 1 Hispanic. Mean weight was 85.0 100
kg (range, 79.2-92.3), mean height was 174.8 cm (range, 50
170.2-177.8), and mean body mass index was 27.8 0
(range, 25.0-30.5). All achieved steady-state valproate 0 5 10 15 20
concentrations above 50 mg/L by day 36 of the study. Time (Hours)
Coadministration of divalproex had minor effects
on the pharmacokinetics of aripiprazole (Table I and Figure 1. Mean plasma concentration versus time profiles of
aripiprazole at steady state following administration of 30 mg of
Figure 2). It decreased the geometric mean AUCτ and aripiprazole alone and with lithium.
Cmax of aripiprazole by 24% and 26%, respectively; it
increased median tmax of aripiprazole by 2 hours and
the CLT/F of aripiprazole by 33%. Coadministration of
divalproex had minimal effects on the pharmaco-
kinetics of dehydro-aripiprazole. It decreased the geo- Due to the small sample size in both studies, both
metric mean AUCτ and Cmax of dehydro-aripiprazole by safety and efficacy could not be adequately deter-
8% and 7%, respectively; it increased the median tmax mined. However, no untoward effects were seen in
of dehydro-aripiprazole by 1.5 hours. EEG, ECG, or clinical laboratory monitoring or in mea-

DRUG INTERACTIONS 91

Aripiprazole alone
Aripiprazole Concentration (ng/mL)
450
400
350
300
250
200
150
100
50
0 the free fraction of aripiprazole may lead to increased
0 5 10
Time (Hours)
Figure 2. Mean plasma concentration versus time profiles of
aripiprazole at steady state following administration of 30 mg of
aripiprazole alone and with valproate.
sures of motor function, psychopathology, or
cognition.
DISCUSSION
Lithium is not bound to plasma proteins or metabo-
lized, and it is excreted almost entirely in the urine in
humans.15 Therefore, a pharmacokinetic interaction is
not expected with aripiprazole. Overall, the data ob-
tained in this study in a limited number of patients in-
dicated that coadministration of lithium with
aripiprazole had no apparent effect on the steady-state
pharmacokinetics of aripiprazole or on the major
aripiprazole metabolite, dehydro-aripiprazole.
Valproate coadministration had minor effects on the
pharmacokinetics of aripiprazole. Valproate is a broad-
spectrum inhibitor of UGT enzymes, epoxide
hydrolase, and CYP2C9 enzymes.18 It has been shown
that coadministration of valproate can increase plasma
concentrations and AUC of lamotrigine, lorazepam,
and carbamazepine-10, 11 epoxide. Valproate does not
inhibit cyclosporine or oral contraceptives, suggesting
a lack of inhibition of CYP3A-metabolized drugs. No
data suggest that valproate is an inhibitor of CYP2D6 or
an inducer of CYP3A4 and/or CYP2D6. Therefore, the
slight increase in the oral clearance of aripiprazole in
the presence of divalproex is not likely due to the in-
duction of the metabolism of aripiprazole, whose major
metabolic pathways are mediated by CYP3A4 and
CYP2D6.
Valproate and/or its unsaturated metabolites can
displace other highly protein-bound drugs.18 The pri-
mary binding site for valproate and its unsaturated me-
92 • J Clin Pharmacol 2005;45:89-93
CITROME ET AL
Aripiprazole + Valproate
tabolites is the diazepam binding site (site II, same as
the aripiprazole primary binding site), but it can also
displace ligands from the warfarin binding site (site
I).19,20 Coadministration of valproate increased the un-
bound fractions of diazepam and phenytoin in hu-
mans.21,22 As valproate and aripiprazole share the same
plasma protein-binding site II, valproate coadmin-
istered with aripiprazole may displace bound
aripiprazole. As aripiprazole is not a high extraction ra-
tio drug, given its high bioavailability,14 the increase in
15 20
oral clearance and therefore a decrease in plasma con-
centrations of total drug, with no change in unbound
plasma drug concentrations.23 The 25% decrease in the
steady-state total aripiprazole Cmax and AUC values af-
ter coadministration of valproate, observed in this
study, is consistent with this hypothesis. Based on
these considerations, the relatively minor changes in
the pharmacokinetics of aripiprazole and its active me-
tabolite observed during valproate coadministration
are not considered clinically significant. Product label-
ing as approved by the Food and Drug Administration
recommends a starting and target dose for aripiprazole
of 10 or 15 mg/d and does not call for dosage adjust-
ment of aripiprazole when administered concomi-
tantly with valproate.14
CONCLUSIONS
Coadministration of lithium or divalproex sodium
with aripiprazole had no clinically significant effect on
the steady-state pharmacokinetics of aripiprazole and
its active metabolite.
Further research regarding the efficacy and safety of
combination therapy versus aripiprazole monotherapy
is needed.
The authors thank Karen Brown, MS, Mohinder Bathala, PhD,
and Michael Gold, MD, of Bristol-Myers Squibb; Eva Kohegyi, MD,
Ashok Joseph, MD, Wynn Wynn Paing, MD, Tomas Watanabee, MD,
and Paul Rapp, PhD, from the Norristown, Pennsylvania, site;
Khurshid Begum, MD, from the Bronx, New York, site; and Eunide
Joseph, RN, BSN, Santha Vaidian, RN, Linda Kline, RN, CS, MS,
Surjit K. Dhami, MD, Biman Roy, MD, William Greenberg, MD, Dan-
iel Javitt, MD, PhD, and Jan Volavka, MD, PhD from the Orangeburg,
New York, site.
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