Pharmacokinetics and Safety of Aripiprazole &

Concomitant Mood Stabilizers

Leslie Citrome, MD, MPH1, Richard Josiassen, PhD2, Nigel Bark, MD3, Karen S Brown, MS4, Suresh Mallikaarjun, PhD5, Daniel E Salazar, PhD4
1Nathan S Kline Institute, Orangeburg, NY, USA; 2Arthur P Noyes Research Foundation, Norristown, PA, USA; 3Bronx Psychiatric Center, Bronx, NY, USA;
4Bristol-Myers Squibb, Wallingford, CT, USA; 5Otsuka Maryland Research Institute, LLC, Rockville, MD, USA

ABSTRACT INTRODUCTION RESULTS

Objective: To assess the pharmacokinetic and
safety profile of aripiprazole, an antipsychotic
with a unique pharmacologic profile of dopamine
D2 partial agonism, serotonin 5-HT1A partial
agonism and 5-HT 2A antagonism, when
coadministered with lithium or divalproex
sodium.
Methods: Two open-label, sequential treatment
design studies were conducted in chronically
institutionalized patients with schizophrenia or
schizoaffective disorder requiring treatment with
lithium (n=7) or divalproex sodium (n=6).
Patients received aripiprazole 30 mg/day on
days 1-14 and aripiprazole with concomitant
therapy on days 15-36. Lithium was titrated from
900 mg until serum concentrations reached
1.0-1.4 mEq/L for >5 days. Divalproex sodium
was titrated to 50-125 mg/L.
Results: Coadministration with lithium increased
mean Cmax and AUC values of aripiprazole by
about 19% and 15%, respectively, while the
apparent oral clearance decreased by 15%.
There was no effect on the steady state
pharmacokinetics of the active metabolite of
aripiprazole. Coadministration with divalproex
sodium decreased the AUC, Cmax, and Cmin of
aripiprazole by 24%, 26%, and 22%,
Antipsychotics are frequently co-
administered with lithium and divalproex
sodium in patients with schizophrenia,
schizoaffective disorder or bipolar
disorder. Because polypharmacy is so
common in the treatment of these
complex psychiatric illnesses, it is
important to evaluate the safety of
aripiprazole coadministration with lithium
and valproate.
Aripiprazole is a newly developed anti-
psychotic with a unique pharmacologic
profile of dopamine D2 partial agonism,
serotonin 5-HT1A partial agonism and
5-HT2A antagonism. Aripiprazole is the
first dopamine partial agonist to
demonstrate rapid and sustained efficacy
in the short and long-term treatment of
schizophrenia. Aripiprazole also has
demonstrated a favorable safety and
tolerability profile of including low potential
for EPS, weight gain, prolactin elevation,
QTc prolongation, and somnolence.
Aripiprazole is extensively metabolized
state, OPC-14857, the active metabolite
represents about 39% of aripiprazole AUC
in plasma.
Lithium is indicated in the treatment of
bipolar disorder. Lithium toxicity is closely
related to serum lithium concentrations
and can occur at doses close to thera-
peutic concentrations. Lithium is not
metabolized, is not bound to plasma
proteins and is excreted almost entirely in
the urine.
Divalproex sodium (valproate) is
indicated for the treatment of the manic
episodes associated with bipolar disorder,
as well as as treatment of complex partial
seizures and for prophylaxis of migraine
headaches. Valproate is a broad-spectrum
inhibitor of CYP 2C9 enzymes. It is also
known that valproate and/or its unsatu-
rated metabolites act as protein binding
displacers with respect to a number of
drugs.
Results are reported from two studies
that assessed the pharmacokinetics and
Aripiprazole + Lithium
+ Pharmacokinetic Effects
– Coadministration of lithium
with aripiprazole had no
apparent effect on the
steady state pharmaco-
kinetics of aripiprazole.
– The mean Cmax and
AUCTAU 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, AUCTAU, and
Fig. 1
systemic clearance values
of aripiprazole in individual
subjects administered
Aripiprazole + Divalproex Sodium
– The results of the MMSE and EEG + Pharmacokinetic Effects decreased AUCTAU, Cmax,
monitoring suggest no evident
– Coadministration of divalproex sodium and Cmin of OPC-14857 by
effects of the combination on had minor effects on the pharmaco- 8%, 7%, and 11%,
cognition, or any lowering of seizure kinetics of aripiprazole. respectively; it increased
threshold. – It decreased the AUCTAU, Cmax, and median Tmax of OPC-14857
– There was no indication of increased Cmin of aripiprazole by 24%, 26%, and by 1.5 h.
laboratory or cardiovascular – These changes in pharmaco-
22%, respectively; it increased
abnormalities. median Tmax of aripiprazole by 2 h kinetics of aripiprazole and
and the systemic clearance of OPC-14857 were not
aripiprazole by 33%. considered clinically
significant.
– Co-administration of divalproex
+ Safety
sodium had minimal effects on the
pharmacokinetics of OPC-14857. It – The coadministration of
aripiprazole 30 mg daily with
therapeutic doses of
divalproex sodium was safe
Aripiprazole + Lithium
Fig. 4
Aripiprazole + Divalproex Sodium and well tolerated.
Mean Plasma Concentration vs Time, Steady State Mean Plasma Concentration vs Time, Steady State – Four subjects discontinued
early: 2 subjects withdrew
1000
their consent, and 2 subjects

Aripiprazole Concentration
respectively, with minimal effects on the active

metabolite.
Conclusion: Aripiprazole can be administered
by the liver via dual metabolic pathways,
CYP 3A4 and CYP 2D6 enzyme systems.
Aripiprazole Concentration
aripiprazole alone and Aripiprazole Alone 1000
safety of the coadministration of lithium aripiprazole with lithium. Aripiprazole + Lithium were discontinued due to AEs
and divalproex sodium with aripiprazole in (i.e., inguinal hernia, hostile
– Coadministration of lithium

(ng/mL)
safely with therapeutic doses of lithium or

(ng/mL)
Aripiprazole is the predominant drug chronically institutionalized patients with behavior).
divalproex sodium in patients with schizophrenia moiety in systemic circulation. At steady schizophrenia or schizoaffective disorder. with aripiprazole also had 100
or schizoaffective disorder. – All AEs reported in the study
no apparent effect on the 2x15 mg Aripiprazole Alone, Day 14
were mild to moderate in
steady state pharmaco- 2x15 mg Aripiprazole with
DivalproexS odium, Day3 6 severity, with the most
kinetics of major 100 10 frequently reported adverse
0 4 8 12 16 20 24
aripiprazole metabolite, 0 4 8 12 16 20 24
events occurring within day 1
METHODS OPC-14857. Time (h)
Time After Dosing (h)
and resolving by day 2.
Lithium-Treated Patients Valproate-Treated Patients + Safety – There was no evidence of
Study Design
+ Two open-label, sequential treatment – Lithium coadministration at deterioration of psychotic
Enrolled Subjects Enrolled Subjects doses ranging from 1200- Fig. 2 Fig. 5 symptoms or cognition, and
design studies Characteristic (n=12) Characteristic (n=10) Aripiprazole + Lithium Aripiprazole + Divalproex
+ Conducted in chronically institutionalized 1800 mg/day with Mean Plasma Concentration of Active Metabolite of Mean Plasma Concentration of Active Metabolite of no increases in EPS.
patients with schizophrenia or Pharmacokinetic Pharmacokinetic aripiprazole was generally Aripiprazole, OPC-14857, Steady State Aripiprazole, OPC-14857, Steady State – The coadministration of
7 6
schizoaffective disorder requiring Sample Sample safe and well tolerated in 1000 1000
aripiprazole 30 mg and

OPC-14857 Concentration
OPC-14857 Concentration
Aripiprazole Alone
treatment with lithium (n=12) or divalproex this study of 12 subjects divalproex sodium did not
Age, years Age, years Aripiprazole + Lithium
sodium (n=10). with schizophrenia or produce any EEG changes of
Mean 36 Mean 33 schizoaffective disorder. clinical relevance in any

(ng/mL)
(ng/mL)
+ Patients received aripiprazole 30 mg/day
SD 9 SD 6 100 100
subject.
on days 1-14 and aripiprazole with – The adverse events
Range 20-47 Range 22-40 2x15 mg Aripiprazole Alone, Day 14
concomitant therapy on days 15-36. reported in this study were 2x15 mg Aripiprazole with
Gender, n (%) Gender, n (%) mild to moderate in
+ Lithium was titrated from 900 mg until
Male 11 (91.7%) Male 10 (100%)
DivalproexS odium, Day3 6
CONCLUSIONS
serum concentrations reached severity, are typical of 10 10
0 4 8 12 16 20 24
Female Female 0 4 8 12 16 20 24
1.0-1.4 mEq/L for >5 days. 1 (8.3%) 0 those observed during Time After Dosing (h)
Time (h) + Coadministration of lithium or
+ Divalproex sodium was titrated to Race, n (%) Race, n (%) monotherapy with
divalproex sodium with
50-125 mg/L. White 7 (58.3%) White 2 (20%) aripiprazole or lithium and
aripiprazole had no clinically
Outcome Measures Black 3 (25%) Black 6 (60%) resolved with discontin-
significant effect on the steady
+ Safety, Tolerability: Hispanic/Latino 2 (16.7%) Hispanic/Latino 2 (20%) uation of therapy. Fig. 3 Fig. 6
Most Frequent Adverse Events Most Frequent Adverse Events state pharmacokinetics of
Monitoring for the occurrence of adverse Weight, kg Weight, kg – There was one serious Incidence in >2 Patients per Treatment Group Incidence in >2 Patients per Treatment Group aripiprazole and its active
events, physical examinations, vital signs, Mean 90.3 Mean 85.7 adverse event of a 100 Aripiprazole 30 mg Aripiprazole 30 mg metabolite, OPC-14857.
clinical laboratory results, ECGs, EEGs, SD 21.8 SD 10.0 confusional state that 90 Aripiprazole + Lithium 100 Aripiprazole + Divalproex Sodium
assessment of extrapyramidal symptoms, 80 + The coadministration of
Range 66.2-143.1 Range 71.1-105.8 occurred after addition of 90

Incidence (%)
PANSS and MMSE. lithium to aripiprazole.
70 80 aripiprazole 30 mg daily and

Incidence (%)
60
Height, cm Height, cm 70
therapeutic doses of lithium or
+ Pharmacokinetics: Careful review of the 50 60
Mean 174.9 Mean 176.9 40 divaproex sodium was safe
Pharmacokinetics of orally administered clinical profile suggests that 30
50
SD 7.5 SD 4.7 40 and well-tolerated.
aripiprazole, its active metabolite OPC- this was a lithium-induced 20
30
Range 167.6-188.0 Range 170.2-182.9 10
14857 and lithium were derived from encephalopathy. 0
0 20 + No electroencephalographic
plasma concentration versus time data. Body Mass Index Body Mass Index Headache Lightheadedness Agitation 10
Anxiety Nausea 0 changes of clinical relevance
The following pharmacokinetic parameters Mean 31.1 Mean 27.5 Agitation Headache Insomnia were produced.
were assessed: Cmax, Tmax, AUCTAU, SD 6.4 SD 3.2
Cmin, and systemic clearance. Range 23.5-42.7 Range 23.6-31.7