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310 Current Clinical Pharmacology, 2014, 9, 310-317

The Pharmacokinetics of Long-Acting Antipsychotic Medications

Stefano Spanarello* and Teresa La Ferla

NHS, Health Trust No. 3 Umbria, Mental Health Department, Day Hospital, Via Arcamone s.n.c., 06034 Foligno,
Perugia, Italia

Abstract: The depot antipsychotics are synthesized by esterification of the active drug to a long chain fatty acid and the
resultant compound is then dissolved in a vegetable oil, with the exception of some molecules of new generation
characterized by microcrystalline technologies. The absorption rate constant is slower than the elimination rate constant
and therefore, the depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function of the
absorption rate, and the concentration at steady-state is a function of the elimination rate The pharmacokinetics of depot
antipsychotic medications are such that an intramuscular injection given at intervals from 1 to 4 weeks will produce
adequate plasma concentrations that are sufficient to prevent relapse over the dosage interval. Such medication is useful in
patients who do not reliably take their oral medication. The pharmacokinetics and clinical actions of various depot
formulations of antipsychotic drugs have been extensively studied. The clinical pharmacokinetics of the depot
antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol
decanoate, bromperidol decanoate, clopenthixol decanoate, flupenthixol decanoate, perphenazine onanthat, pipotiazine
undecylenate, pipotiazine palmitate, fluspirilene, Long-acting injectable risperidone, olanzapine pamoate, paliperidone
palmitate, Long-acting iloperidone, Long-acting injectable aripiprazole) are reviewed. The proper study of these agents
has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma.
Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to
injectable therapy are discussed.
Keywords: Absorption, antipsychotics, kinetics, long-acting, plasma level, relapse.

INTRODUCTION and a low one in water, are placed in oily solution, initially
in sesame oil. The oil, when is injected intramuscularly,
The evidence, in psychotic patient, of poor compliance
forms a deposit of drug: the ester of the drug diffuses slowly
with traditional neuroleptic therapies, shown immediately
into the blood and is quickly hydrolyzed by the esterases,
after their introduction by Laborit, Delay and Deniker in
releasing the active principle drug. The majority of second
1954, stimulated, since the Sixties, two lines of research,
generation antipsychotic drugs (SGAs) show a lack of
conducted by one side at the synthesis of very long half-life
terminal -OH groups for the esterification. The modification
molecule, by the other at the modification of existing of release parameters has been obtained by other strategies,
molecules by Galenic tricks, to delay its release. The first
such as the drug encapsulation in a biodegradable polymer
line of research led to the synthesis, in 1968, of penfluridol, a
(risperidone, iloperidone, aripiprazole) or injection of an
diphenylbutylpiperidine antipsychotic, characterized by a
aqueous suspension of the insoluble compound in the water
half-life that, in the second phase of elimination, settles
(olanzapine pamoate, paliperidone palmitate).
between 4 and 10 days [1]. The second line of research led,
in 1964, to the introduction of fluphenazyne enanthate, the GENERAL PHARMACHOKINETICS OF LONG-
first depot neuroleptic, and after short time, fluphenazyne ACTING ANTIPSYCHOTIC
decanoate, perphenazine enanthate, flupenthixol decanoate,
The mechanism by which the long-acting antipsychotics
pipotiazine undecylate and palmitate, haloperidol decanoate
are absorbed slowly from the injection site after the
and zuclopenthixol acetate and decanoate. The chemical
administration, is not so clear yet and the recent reporting of
characteristic shared by all of these molecules is the presence
olanzapine pamoate post-injective syndrome has put the
of a terminal alcoholic group (-OH), which allows them to
be combined with carboxylic acids by a process of interest on uptake and release mechanisms again. In the case
of long-acting antipsychotics containing esterified chain,
esterification, according to the reaction neuroleptic-OH +
about the 95% of the injected product remains in the injected
HOOC – (CH2)n-CH3>H2O + neuroleptic – O - CO – (CH2)n-
zone [2]. The other part is divided between skin, bone and
CH3. Such esters of neuroleptics, with a high solubility in oil
visceral tissues, playing an insignificant role in the
mechanism of drug slow release [2, 3]. About the visceral
distribution of drugs, we find the highest concentrations in
*Address correspondence to this author at the NHS, Health Trust No. 3 the liver, the kidney, the intestines and the stomach, while
Umbria, Mental Health Department, Day Hospital, Via Arcamone s.n.c.
06034 Foligno, Perugia, Italia; Tel: 39-340-8201814;
we find lower levels in the heart and in the brain [2, 3]. The
E-mail: [email protected] esters of the antipsychotics undergo an enzymatic hydrolysis

2212-3938/14 $58.00+.00 © 2014 Bentham Science Publishers

The Pharmacokinetics of Long-Acting Antipsychotic Medications Current Clinical Pharmacology, 2014, Vol. 9, No. 3 311

in the body which follows the drug release. The esters that Viscoleo. Another study [8], in which the radio-labeled oil
are beyond the enzymatic hydrolysis before being excreted was injected in the dog, showed that the radioactivity
in unchanged form, have no effects on the pharmacokinetics disappeared from the injection site after two days from the
of the molecule. Many tissues contain esterases that can radio-labeled Viscoleo administration and after five weeks
hydrolyse these esters, however, the hydrolysis rate changes from the radio-labeled sesame oil administration. The same
depending on the used ester and on the tissue [2, 3]. For study showed that chronic administration of both oils led to
some product, the duration of action increases with the their absorption through the lymphatic system to the lungs as
elongation of the esterifying acid chain, while the duration of microemboli [8]. The release of the active principle depends,
action of the active principle after its release is probably the in particular, on the prodrug hydrolysis by the esterase in the
same. The free form from neuroleptics in the central nervous injection site, as the oil protects the ester from the esterases
system, can originate from other tissue where the hydrolysis action [9]. A limiting factor of released drug can be
has occurred and its subsequent release or to a lesser extent represented by the diffusion rate of the same from the oily
from the ester hydrolysis in the brain tissue, where there are solution. The migration of the prodrug with the oily solution
esterases [2, 3]. The esters, in fact, because of their high lipid from the injection site to the lymphatic system can be
solubility should cross the blood-brain barrier at least as another important factor [10]. A study [11] in which
good as the free forms [4]. We cannot exclude [5] the radio-labeled clopentixole decanoate in sesame oil was
possibility that the presence of small amounts of ester in the administered to dogs and rats evidenced a nano-exponential
brain could cause some small qualitative differences between release from the depot with a half-life of 4-5 days. By
the activities of these esters and the correspondents contrast, in vitro studies showed that the hydrolysis of the
antipsychotics, as has been clinically observed. In fact the ester of clopentixole occurs rapidly in a large variety of
physical-chemical properties of the esters and, in particular, tissues, including muscle tissue [9]. Similar experiments
their lipid solubility are different from those of the basic carried out with marked Fluphenazine decanoate showed that
products and the esters could be distributed differently in the the 18.6% of the dose of drug was present in the injection
various area of the brain before being hydrolyzed. In relation site after 35 day from the administration [9]. Another
to the vehicle oily solution or suspension, however, the important aspect is the role of the lymphatic system. Studies
duration of action of an ester is longer in oily solution with radio-labeled oily vehicles have shown their presence in
compared to the aqueous solution. The concentration of ester the lymph nodes of experimental animals. Radio-labeled
in oily solution also influence the drug kinetic in a direct haloperidol decanoate were detected in lymphnodes from
proportion. Certainly the viscosity of the vehicle plays a various parts of the body of rats after 50mg/kg of 14 C-
central role in the absorption of the drug. The two most Haloperidol was given intramuscularly, which suggested that
frequently used vehicles are the sesame oil and the Viscoleo haloperidol decanoate was partially absorbed by lymphatic
(Table 1). system [12]. The same research team reported that the
hydrolysis of haloperidol decanoate in vivo was markedly
inhibited in presence of macromolecules such as β -
Table 1. FGA depot preparation containing prodrug. lipoprotein or albumin [13]. The strong interaction between
haloperidol decanoate and these proteins protected the ester
FGA Vehicle Preparation against enzymatic hydrolysis [13]. Second generation long-
acting antipsychotics, none of which utilizes the oily vehicle,
Fluphenazine Decanoate Ester Sesame Oil are absorbed through a different mechanism. The absorption
Enantate Ester Sesame Oil vehicles of SGA long-acting antipsychotics are reported in
Table 2.
Haloperidol Decanoate Ester Sesame Oil
ZuClopenthixol Acetate Ester Viscoleo
Decanoate Ester Viscoleo Table 2. SGA long-acting preparations containing prodrug.
Flupenthixol Decanoate Ester Viscoleo
Pipothiazine Undecylate Ester Viscoleo SGA Vehicle Preparation
Palmitate Ester Viscoleo Risperidone Microspheres Water
Bromperidol Decanoate Ester Sesame Oil
Olanzapine Salt (pamoate) Water (microcrystalline suspension)
Perphenazine Enantate Ester Sesame Oil
Paliperidone Ester (palmitate) Water (nanosuspension)
Decanoate Ester Sesame Oil
Fluspirilene Microspheres Water
The Risperidone LAI (long acting injection) uses
microspheres that gradually dissolve themselves, releasing
The coefficient of oil/water partition is one of the most the active compound in circulation. The absorption is slow
important parameters in this area [6]. In a small study [7] of and it reaches peak plasma level after two weeks and the nit
two patients treated with perphenazine decanoate in two requires a transition with oral risperidone for two weeks
different oil solutions (sesame oil and viscoleo) higher initially [14, 15]. Olanzapine LAI is the salt of pamoic acid
plasma concentrations of drug have been observed in the and olazapine, that is suspended in an aqueous solution
subject treated with perphenazine decanoate in sesame oil. It injected into the gluteus. When it is injected into the gluteal
was found that sesame oil is degraded more slowly than muscle, the two components of the salt slowly dissociate
312 Current Clinical Pharmacology, 2014, Vol. 9, No. 3 Spanarello and La Ferla

themselves in particular molecular compounds, olanzapine the blood is greater than 90%. Bromperidol is metabolized
and pamoic acid [16, 17]. The rate of salt dissolution is slow, by ketone reduction, N-dealkylation (catalyzed by CYP3A4)
allowing a gradual release of olanzapine in 2-4 weeks [16]. and glucuronidation. Excretion is 60% with the faeces, and
The absorption of paliperidone LAI is based on the palmitate 40% by urine [24]. Treatment is usually started with a dose
ester of paliperidone, that is an aqueous suspension that uses of 50 mg and maintenance doses are usually in the range 50–
molecules of nanocrystals. [18, 19]. This formulation 300 mg every 4 weeks [24].
increases its surface area and leads to the initial phase of the
Haloperidol Decanoate
rapid release and in a short time at the steady-state. The low
rate of dissolution of paliperidone palmitate results in a The depot preparation of haloperldol is an ester of
longer half-life, ranging from 25 to 49 days, allowing an haloperidol and decanoic acid in sesame oil. Haloperidol
intramuscular injection once a month [18, 19]. Another decanoate plasma concentrations peak on the seventh day
preparation recently studied is the slow-released aripiprazole. following injection although, in some patients, this peak may
D-optimal mixture design was employed to design and occur on the first day [25]. The apparent elimination half-life
optimize long-acting depot injection of aripiprazole using after multiple injections is approximately 3 weeks and the
polylactide-co-glycolide (PLGA) 50:50, 75:25, 85:15, and time to reach steady-state is approximately 3 months.
cholesterol as release rate-retarding material. Desirability Haloperidol decanoate is slowly released into the circulation
technique was used to optimize formulations. Predicted where it is hydrolyzed releasing active haloperidol. Peak
optimized formulation was experimentally validated and it plasma concentration occur within 3-9 days, then decrease
was found that the developed formulation releases the drug slowly [26]. Haloperidol decanoate undergoes hydrolysis by
for a 14-day time period. The optimized formulation showed plasma and/or tissue esterases to form haloperidol and
that the cholesterol-containing formulation exhibits a better decanoic acid [26]. Subsequently, haloperidol is metabolised
drug release profile [20]. The pharmacokinetic studies in the liver, the main route of metabolism being oxidative N-
confirmed that the developed cholesterol-based depot dealkylation, and reduction of the ketone group to form
formulation was capable of releasing the drug for a time reduced haloperidol [27]. Reduced haloperidol is much less
period of more than 14 days [20]. The implant formulation active than haloperidol but undergoes re-oxidation to
was sterilized by gamma radiation and ethylene oxide haloperidol [28, 29]. The cytochrome P4502D6 has been
sterilization method. The D-optimal mixture design was shown to be involved in the oxidative metabolic pathway
proved to be an efficient technique for the formulation and [30]. For haloperidol decanoate no formal test dose is
optimization [20]. specified. Treatment is usually started with a dose of 50 mg
and maintenance doses are usually in the range 50–300 mg
The absorption rate constant is slower than the
every 4 weeks. Doses of around 100 mg every 4 weeks are
elimination rate constant and therefore older depot FGA
antipsychotics exhibit ‘flip-flop’ kinetics where the time to probably optimal [31].
steady-state is a function of the absorption rate, and the Diphenylbutylpiperidines
concentration at steady-state is a function of the elimination
Fluspirilene
rate [21]. One additional aspect of all injectable medications
is that they avoid first pass metabolism, conceivably Long Acting Fluspirilene can be synthesized starting
resulting in lower circulating metabolites than are after oral from benzyl-piperidone and aniline. The molecule was
administration [22] and in longer accumulation half-life than synthetized in 1963 for intramuscular use only. It was the
their oral counterparts. Long-acting injectable antipsychotics first extended release antipsychotic not synthesized in an
require therefore more time to reach stable steady state and a esterified form, not possessing an alcoholic terminal, but in
longer time to disappear from plasma after termination of the form of micronized preparation to slow absorption.
treatment [23]. Fluspirilene is administered by intramuscular injection of
microcrystalline preparation in aqueous suspension [32]
OUTLINE OF SINGLE LONG ACTING ANTI- at intervals of 7-10 days until two weeks. It is rapidly
PSYCHOTIC MEDICATIONS PHARMACOKINETIC
metabolized, from the injection site to other tissues and it is
AND PHARMACODYNAMICS PROPERTIES
excreted through the kidneys, so the main metabolite of 4,4-
First-Generation LAIs bis (4-fluorophenyl) butyric acid is obtained by N-
dealkylation and expelled in the urine. The onset of action is
Butyrophenones
4 hours [32].
Bromperidol Decanoate Phenothiazines
Bromperidol decanoate is an ester of bromperidol and
Fluphenazine Enanthate and Decanoate
decanoic acid. The ester is gradually hydrolyzed in the
body by an enzymatic process by which carbon is released Fluphenazine is available as both an enanthate and
[24]. During once-monthly administration of bromperidol decanoate ester (both dissolved in sesame oil), although the
decanoate, steady-state plasma bromperidol concentrations decanoate is of more common clinical use. The enanthate
were attained after 3 months and the plasma half-life produces peak plasma concentrations on days 2 to 3 and
was about 3 weeks. After deep intramuscular injection, declines with an apparent elimination half-life of 3.5 to 4
bromperidol asset is slowly released, so that blood levels are days after a single injection. The decanoate produces an
reached in six days [24]. The half-life (t½ß) is 25 days on early high peak which occurs during the first day and then
average. The kinetic of release of bromperidol decanoate declines with an apparent half-life ranging from 6.8 to 9.6
form unfolds like that of bromperidol, binding to proteins in days following a single injection [33]. After multiple
The Pharmacokinetics of Long-Acting Antipsychotic Medications Current Clinical Pharmacology, 2014, Vol. 9, No. 3 313

injections of fluphenazine decanoate, however, the mean defined. The optimal dose of pipotiazine palmitate was
apparent half-life increases to 14.3 days, and the time to between 100 mg and 600 mg every 4 weeks, as suggested by
reach steady-state is 4 to 6 weeks [33]. Cigarette smoking early studies [48]. Later trials found doses of 50–200 mg
has been found to be associated with a 2.33-fold increase in every 4 weeks to be effective as well [45-47].
the clearance of fluphenazine decanoate [34]. In 3 different
studies, fluphenazine has been proposed to have a Thioxantines
therapeutic range from < 0.15 to 0.5 ng/ml with an upper Flupenthixol Decanoate
therapeutic range of 4.0 ng/ml. Plasma concentrations
following the decanoate injection are generally lower than, Flupenthixol is available as either the palmitate or
but clinically equivalent to those attained with the oral form decanoate ester, although most pharmacokinetic studies
of the drug. Fluphenazine decanoate is the decanoate ester of have used the decanoate formulation. Like clopenthixol,
a trifluoromethyl derivative, in sesame oil preparation. Only flupenthixol is only active as the cis (Z) isomer which is the
few studies about fluphenazine decanoate levels have used form present in the decanoate preparation. Peak plasma
single-dose strategies [34-37] and obtained blood samples at concentrations occur on approximately the seventh day
enough time points during the injection interval [35, 38, 39] following injection, and no pharmacokinetic differences
to allow conclusions about the steady-state pharmacokinetic have been observed between 2% and 10% concentrations
profile of Fluphenazine decanoate. Fluphenazine decanoate of the drug. Following a single injection, an apparent
is initiated with a test dose of 12.5 mg [40]. Maintenance elimination half-life of 8 days was reported, whereas after
doses are in the range 12.5–100 mg given every 2–5 weeks – multiple injections, the apparent half-life was 17 days. No
the maximum dose is thus 100 mg every 2 weeks. Much correlations between plasma concentrations and clinical
lower doses appear to be effective – 25 mg every 2 weeks is response were found [49]. Flupentixol decanoate is given
no more effective than 25 mg every 6 weeks. There is some initially as a test dose of 20 mg. After 7 days a further dose
support for even lower doses, but controlled trials suggest of 20–40 mg is administered. Dosing is then at intervals of
that doses substantially less than 25 mg every 2 weeks 2–4 weeks, at doses ranging from 50 mg every 4 weeks to
greatly increase the risk of relapse [7, 41]. 400 mg weekly [49]. Dose–response relationships are less
than clear. One study showed 40 mg every 2 weeks to be as
Perphenazine Enantate and Decanoate effective in relapse prevention as 40 mg every 4 weeks [50].
Perphenazine is a piperazine phenothiazine available as Two other double blind trials offered some support to the use
either the enantate or decanoate ester in sesame oil, of 40 mg every 2 weeks as the optimal dose of this
historically employed first in northern Europe and compound. In one study, 40 mg every 2 weeks was shown to
Scandinavia. Peak plasma levels are obtained in 1–7 days, be as effective in improving `ward behaviour' and better
with an half-life of approximately 2 weeks [7]. Steady-state tolerated than 200 mg every 2 weeks in female patients over
levels are reached after 3 months. During regular dosing 13 weeks' treatment [51]. In the other study a 50% dose
there are small, dose-related variations in plasma levels [41]. reduction to 6 mg per week led to a considerably increased
A good therapeutic response has been associated to risk of relapse compared with participants not undergoing
Perphenazine plasma levels of 1–5 nmol/l, although a higher dose reduction receiving on average 9 mg per week [52]. In
therapeutic range has been suggested [42]. The minimum contrast, another double blind randomized trial in patients
effective dose of perphenazine decanoate was found to be stabilized on higher doses showed that reducing the dose of
about 100 mg every 2 weeks (range 21.6–270.5 per 2 weeks) flupentixol below 200 mg every 2 weeks significantly
[43]. Plasma levels ranged from around 2 nmol/l to 18 increased the risk of relapse [53].
nmol/l depending on dose [7]. Plasma levels averaged 5
Zuclopenthixol Decanoate and Acetate
nmol/l and ranged from around 2 nmol/l to 6 nmol/1 in a
further study of responding patients receiving 108.5 mg For some years, the cis-(Z)-zuclopenthixol has been
perphenazine decanoate every 2 weeks [41]. Doses of around available in the form of two different injectable preparations
100 mg every 2 weeks are effective and provide plasma in addition to oral preparations. The first one is a solution of
levels in the range 3–11 nmol/l [7, 41]. the acetate acid ester of zuclopenthixol in vegetable oil,
Viscoleo and was developed for the treatment of acute
Pipotiazine Palmitate and Undecylate
psychotic episodes, while the second preparation was a
Pipotiazine palmitate is the palmitic ester of pipotiazine, solution of the decanoic acid ester of zuclopenthixol in
a piperidine phenothiazine with antipsychotic properties and Viscoleo, aimed at maintenance treatment [4, 54, 55]. In
weak sedative activity with prolonged duration of action, clinical studies, zuclopenthixol acetate activity appeared
available in the form of undecylenic ester (Piportil M2) or within few hours, with therapeutic efficacy lasting for 2-3 days
palmitic ester (Piportil L4) [44, 45]. The onset of action [56]. An interesting observation was that the zuclopenthixoles,
appears within 2 to 3 days after injection and the effects of drugs dissolved in a vegetable oil, appeared to be better
the drug on psychotic symptoms are significant within one tolerated at the injection site than earlier aqueous solutions
week. Improvement in symptomatology lasts from 3 to 6 of neuroleptics, that caused local muscle damage [57]. Peak
weeks, but adequate control may frequently be maintained plasma concentrations is usually reached between 4 and 7
with one injection every 4 weeks [45-47]. Pipotiazine days after injection in decanoate preparations. The apparent
palmitate is usually first given as a test dose of 25 mg. elimination half-life after multiple injections is 19 days. No
Maintenance doses are usually within the range 50–200 mg correlation between plasma concentrations and clinical
every month [48]. The dose–response relationship is poorly response has been reported, but concentrations have been
314 Current Clinical Pharmacology, 2014, Vol. 9, No. 3 Spanarello and La Ferla

observed to range from 10 to 100 ng/ml following a wide older oil-based depot formulations, this method allows
range of dosages and injection intervals [4, 54-56]. nanosuspension of paliperidone palmitate in an aqueous
formulation [17, 18]. After administration of paliperidone
Second-Generation LAIs
palmitate, the isotonic aqueous buffer easily penetrates the
Aripiprazole LAI muscle tissue, after which the undissolved paliperidone
palmitate particles are localized at the site of injection as an
Long acting injectable aripiprazole microsphere is a agglomerate. Due to their extremely low water solubility,
phase III investigational drug that was being reviewed by the paliperidone palmitate particles then dissolve very slowly
FDA in 2011. This formulation appears to be similar to into the interstitial fluids at the site of intramuscular
risperidone LAI. The active antipsychotic differs, however, injection, before being hydrolyzed by esterases to palmitic
from risperidone LAI in side effect profile and pharma- acid and the active compound paliperidone [17, 18].
cokinetics. As the pharmaceutical science of microsphere Esterases are muscle-occurring enzymes that catalyze the
construction allows many variations – that were reviewed in hydrolysis of organic esters, such as those found in lipid, to
the section of General Pharmacokinetics of long-acting release an alcohol or thiol or an acid [17, 18]. In this way,
antipsychotics - it is not possible to determine the strengths paliperidone enters the systemic circulation over an extended
and weaknesses of aripiprazole LAI compared with period of time of 125–245 days. The median apparent half-
risperidone LAI microspheres at this time. The dosing life of paliperidone following a single-dose administration of
intervals currently under investigation are 14 and 28 days paliperidone palmitate over the dose range of 39–234 mg
[58]. ranged from 25–49 days, and five times the effective half life
Iloperidone LAI is required for 97% completion of a first-order process [17,
18]. This allows for once-monthly dosing without the need
Iloperidone LAI is a phase III investigational drug. FDA for oral supplementation. Paliperidone palmitate is available
registration documents and early publication and in dose strengths of 25, 50, 75, 100 or 150 milligram
presentation data report that iloperidone LAI will be a equivalents, mg eq. The strengths, expressed as 25, 50, 75,
crystalline salt structure pharmaceutically similar to 100 and 150 mg eq. paliperidone, equate to 39, 78, 117, 156
paliperidone and olanzapine LAI formulations. The dosing or 234 mg paliperidone palmitate, respectively. [17, 18, 60].
interval under investigation is 28 days [59]. The absorption component of this model allowed a fraction
Olanzapine Pamoate of the dose to enter relatively quickly into the central
compartment via a zero-order process. The remaining
Olanzapine LAI is a salt of pamoic acid and olanzapine fraction then enters the systemic circulation via a first-order
(olanzapine pamoate) suspended in water. This formulation process after a certain lag time [17, 18]. The population PK
provides peak plasma levels some 2–4 days after model has been used to determine initiation and maintenance
intramuscular administration, with a plasma half-life of 2–4 treatment regimens for paliperidone palmitate and to design
weeks. Plasma levels obtained are directly proportional to dosing strategies for missed dosing scenarios and switching
dose given and time to steady state is around 2–3 months. In from other antipsychotics [18]. In addition, this model has
2-weekly dosing trough levels are around 50% of peak level; been prospectively validated, wherein the model was used to
in monthly dosing trough levels are 75% lower than peak successfully design and predict the anticipated pharma-
[17]. Olanzapine pamoate dissociates readily in aqueous cokinetics from an optimized initiation regimen [60].
environments (e.g. plasma) so its pharmacokinetic properties
depend on the method of administration. The long-acting Risperidone LAI
drug is constituted by the combination of a molecule of The long-acting formulation of risperidone was
olanzapine and pamoic acid molecule in the form of crystal developed by using the “microsphere” technology, in which
salt. The solubility of olanzapine is thus reduced, which the active drug is encapsulated in a lactide, glycolide
gives its kinetic properties: the salts, after deep injection into biodegradable polymer. The microspheres, whose size is
the gluteal muscle slowly dissolve and release the active approximately one tenth of millimeter in size, are added to a
drug for more than four weeks. Unlike risperidone LAI, the saline-base solution and injected into the muscle, where the
active drug is immediately available after administration, polymer gradually degrades over time, allowing the release
with no need for the patient to take supplemental oral of active risperidone with lactic acid and water [15, 61]. The
olanzapine at the beginning of treatment. In addition, the kinetic study of drug release shows that, after a brief phase
interval between injections is wider with olanzapine than release of risperidone present on the surface microspheres
risperidone (one to two monthly injections against an (less than 1% of the dose total), it takes about three weeks
injection every two weeks). Clinical studies on olanzapine (period when the patient is treated with oral medication)
strongly indicate a relationship between clinical outcomes before the start of the actual release phase [61]. The
and plasma concentrations [17]. Olanzapine therapeutic drug fluctuations in plasma concentration risperidone are, during
monitoring, with a therapeutic range of 20-50 ng/mL, can be this phase, smaller than those observed during oral
considered very useful in assessing therapeutic efficacy and administration of risperidone. Risperidone LAI is injected,
controlling adverse events [17]. through a secure provided by the manufacturer, every two
Paliperidone Palmitate weeks either in gluteus or into the deltoid muscle (these
sites are interchangeable). The pharmacological effects of
Paliperidone palmitate is a nearly insoluble ester. risperidone depend on the sum of the plasma concentrations
Through the wet grinding of paliperidone palmitate the of risperidone and its 9-hydroxyrisperidone metabolite, so
surface area is increased, creating nanoparticles. Unlike monitoring the plasma concentrations of the parent
The Pharmacokinetics of Long-Acting Antipsychotic Medications Current Clinical Pharmacology, 2014, Vol. 9, No. 3 315

Table 3. Outline of the main relevant pharmacokinetic parameters of FGA and SGA LAIs.

LAI Test Dose (mg) Peak Concentration Biological Half- Stable plasma Usual Single Interval Dosage
(Days) life (Days) Concentration Dose (mg) (Weeks)
(Months)

Haloperidol Decanoate not recommended 7 21 2–3 25–150 2–4

Bromperidol not recommended 3- 9 25 3 50–300 25
Decanoate not recommended 1 1 (20 h) 3 (days) 50 -150 3 (days)
Zuclopenthixol Acetate 100 7 14 2 100–400 2–4
Zuclopenthixol Decanoate 20 3–7 17 2 20–80 2–4
Flupenthixol Decanoate 12,5 1 7–14 2 12.5 – 75 2–5
Fluphenazine Decanoate not recommended 2–3 1 -7 3 50 – 150 1–2
Perphenazine Enantate not recommended 1–7 1–7 3 50 – 150 2–4
Perphenazine Decanoate 25 3 15 - 60 2 - -
Pipotiazine Palmitate 2 1 - - 50–200 3-4
Fluspirilene - - 21 3 4 – 10 1
Risperidone LAI not recommended 28 4–6 2 25–50 2
Olanzapine Pamoate not recommended 2–4 14–28 2–3 150 – 300 4
Paliperidone Palmitate not recommended - - - 50 - 150 4

compound alone can lead to erroneous interpretations [62]. [2] Jann MW, Ereshefsky L, Saklad SR. Clinical pharmacokinetics of
Despite a large variability in plasma drug concentrations, the the depot antipsychotics. Clin Pharmacokinet 1985; 10: 315-33.
[3] Marder SR, Van Putten T, Mintz J, Lebell M, McKenzie J, May
lack of studies using fixed dosages, and discrepancies in the PR. Low- and conventional-dose maintenance therapy with
results, it seems that monitoring the plasma concentrations fluphenazine decanoate. Two-year outcome. Arch Gen Psychiatry
of the active moiety may be useful [62]. However, no 1987; 44: 518-21.
therapeutic plasma concentration range for risperidone [4] Jørgensen A, Overo KF. Clopenthixol and flupenthixol depot
preparations in outpatient schizophrenics. III. Serum levels. Acta
has yet been clearly established. The threshold plasma Psychiatr Scand Suppl 1980; 279: 41-54.
concentration for extrapiramidal side effects has been found [5] Simon P, Fermanian J, Ginestet D, Goujet MA, Péron-Magnan P.
to be 74 ng/mL. Moreover, therapeutic drug monitoring may Standard andlong-acting depot neuroleptics in chronic
be particularly useful in the switch between the oral and the schizophrenics: an 18-month openmulticentric study. Arch Gen
long-acting injectable form [61-63]. Psychiatry 1978; 35(7): 893-7.
[6] Szukalski B, Lipska B, Welbel L, Nurowska K. Serum levels and
clinical response in long-term pharmacotherapywith zuclopenthixol
CONCLUSION decanoate. Psychopharmacology (Berl) 1986; 89(4): 428-1.
[7] Knudsen P, Hansen LB, Hojholdt K, Larsen NE. Long-term depot
In conclusion, First Generation LAIs guarantee a neuroleptic treatment with perphenazine decanoate. I. Efficacy and
reduction of relapses and show good stability in blood level side effects in a 12 month study of 42 drug monitored psychotic
but they are limited by the onset of iatrogenic effects in the patients. Acta Psychiatr Scand Suppl 1985; 322: 29-40.
[8] Jørgensen A. Pharmacokinetic studies in volunteers of intravenous
long term, in particular extrapyramidal symptoms. Second and oral cis(Z)-flupentixol and intramuscular cis (Z)-flupentixol
Generation LAIs appear, actually, safe and effective decanoate in Viscoleo. Eur J Clin Pharmacol 1980; 18(4): 355-60.
especially olanzapine pamoate and paliperidone palmoate, [9] Dreyfuss J, Shaw JM, Ross JJ Jr. Fluphenazine enanthate and
which give a stability in blood and do not require a fluphenazine decanoate: intramuscular injection and esterification
simultaneous oral intake for the attainment of steady steate. as requirements for slow - release characteristics in dogs. J Pharm
Sci 1976; 65(9): 1310-5.
Table 3 shows the main relevant pharmacokinetic parameters [10] Oh-e Y, Miyazaki H, Matsunaga Y, Hashimoto M. Pharmacokinetics
of First and Second Generation Long Acting Antipsychotics. of haloperidol decanoate in rats. J Pharmacobiodyn 1991; 14(11):
615-22.
CONFLICT OF INTEREST [11] Aaes-Jorgensen T, Overo KF, Bogeso KP, Jorgernsen A.
Pharmacokinetic studies on clopentixol decanoate; a comparison
The authors confirm that this article content has no with clopenthixol in dogs and rats. Acta Pharmacol Toxicol
conflict of interest. (Copenh) 1977; 41(2): 103-20.
[12] Matsunaga Y, Nambu K, Oh-e Y, Miyazaki H, Hashimoto M.
ACKNOWLEDGEMENTS Absorption of intramuscularly administered [14C]haloperidol
decanoate in rats. Eur J Drug MetabPharmacokinet 1987; 12(3):
Declared none. 175-81.
[13] Nambu K, Miyazaki H, Nakanishi Y, Oh-e Y, Matsunaga Y,
REFERENCES Hashimoto M. Enzymatic hydrolysis of haloperidol decanoate and
[1] Janssen PA, Niemegeers CJ, Schellekens KH, et al. The its inhibition by proteins. Biochem Pharmacol 1987; 36(10): 1715-22.
pharmacology of penfluridol (R 16341) a new potent and orally [14] Ramstack M, Grandolfi GP, Mannaert E, D'Hoore P, Lasser RA.
long-acting neuroleptic drug. Eur J Pharmacol 1970; 11(2): 139-54. Long-acting risperidone: prolonged-release injectable delivery of
316 Current Clinical Pharmacology, 2014, Vol. 9, No. 3 Spanarello and La Ferla

risperidone using Medisorb microsphere technology. Schizophr [37] Chang SS, Javaid JI, Dysken MW, Casper RC, Janicak PG, Davis
Res 2003; 60 (suppl 1): 314. JM. Plasma levelsof fluphenazine during fluphenazine decanoate
[15] Kane JM, Eerdekens M, Lindenmayer JP, Keith SJ, Lesem M, treatment in schizophrenia. Psychopharmacology (Berl) 1985;
Karcher K. Long-acting injectable risperidone: efficacy and safety 87(1): 55-8.
of the first long-acting atypical antipsychotic. Am J Psychiatry [38] Midha KK, Hubbard JW, Marder SR, et al. The sulfoxidation of
2003; 160: 1125-32. fluphenazine in schizophrenic patients maintained on fluphenazine
[16] Lauriello J, Lambert T, Andersen S, Lin D, Taylor CC, McDonnell decanoate. Psychopharmacology (Berl) 1987; 93(3): 369-73.
D. An 8-week, double-blind, randomized, placebo-controlled study [39] Nasrallah HA, Rivera-Calimlin L, Rogol AD. Fluphenazine decanoate:
of olanzapine long-acting injection in acutely ill patients with plasmaconcentrations and clinical response [proceedings].
schizophrenia. J Clin Psychiatry 2008; 69: 790-9. Psychopharmacol Bull 1978; 14(3): 46-7.
[17] Kurtz D, Bergstrom R, McDonnell D, Mitchell M. Pharmacokinetics [40] Altamura AC, Curry SH, Montgomery S, Wiles DH. Early
(PK) of multiple doses of olanzapine long-acting injection (OLAI), unwanted effects of fluphenazine esters related to plasma fluphenazine
an intramuscular (IM) depot formulation of olanzapine (OLZ), in concentrations inschizophrenic patients. Psychopharmacology
stabilized patients with schizophrenia. Biol Psychiatry 2008; (Berl) 1985; 87(1): 30-3.
63(suppl 1): 228S. [41] Knudsen P, Hansen LB, Larsen NE. Perphenazine decanoate in
[18] Samtani MN, Kern-Sliwa J, Haskins JT. Initiation dosing of sesame oil vs. perphenazine enanthate in sesame oil: a comparative
deltoid intramuscular paliperidone palmitate in schizophrenia: study of pharmacokinetic properties and some clinical implications.
pharmacokinetic rationale based on modeling and simulation. Acta Psychiatr Scand Suppl 1985; 322: 11-4.
Annual Meeting of the College of Psychiatric and Neurologic [42] Larsen NE, Hansen LB. Prediction of the optimal perphenazine
Pharmacists, Jacksonville, FL, USA, April 19–22, 2009. Poster no. 19. decanoate dose based on blood samples drawn with the first three
[19] Samtani MN, Vermeulen A, Stuyckens K. Population pharma- weeks. Ther Drug Monitor 1989; 11(6): 642-6.
cokinetics of intramuscular paliperidone palmitate in patients with [43] Mazure CM, Nelson JC, Jatlow PI, Kincare P, Bowers MB Jr. The
schizophrenia: a novel once monthly, long-acting formulation of an relationship between blood perphenazine levels, early resolution of
atypical antipsychotic. Clin Pharmacokinet 2009; 48: 585-600. psychotic symptoms, and side effects. J Clin Psychiatry 1990;
[20] Nahata T, Saini TR. Formulation optimization of long-acting depot 51(8): 330-4.
injection of aripiprazole by using D-optimal mixture design. PDA J [44] Kistrup K, Gerlach J, Aaes-Jorgensen T, Larsen NE. Perphenazine
Pharm Sci Technol 2009; 63(2): 113-22. decanoate and cis(z)-flupentixol decanoate in maintenance
[21] Altamura AC, Sassella F, Santini A, Montresor C, Fumagalli S, treatment of schizophrenic outpatients. Serum levels at the minimum
Mundo E. Intramuscular preparations of antipsychotics: uses and effective dose. Psychopharmacology (Berl) 1991; 105: 42-8.
relevance in clinical practice. Drugs 2003; 63: 493-512. [45] Gallant DM, Mielke D, Bishop G, Oelsner T, Guerrero-Figueroa R.
[22] Marder SR. The role of dosage and plasma levels in neuroleptic Pipotiazine palmitate: an evaluation of a new long acting
relapse prevention. Acta Psychiatr Scand Suppl 1994; 382: 25-27. intramuscular antipsychotic agent in severely ill schizophrenic
[23] Marder SR. Depot neuroleptics: side effects and safety. J Clin patients. Dis Nerv Syst 1975; 36: 193-6.
Psychopharmacol 1986; 6(1 Suppl): 24S-29S. [46] Burch EA, Ayd FJ. Depot pipotiazine 1970–1982: a review. J Clin
[24] Benfield P, Ward A, Clark BG, Jue SG. Bromperidol: A Psychiatry 1983; 44: 242-7.
Preliminary Review of its Pharmacodynamic and Pharmacokinetic [47] Girard M, Granier F, Schmitt L, Cotonat J, Escande M, Blanc M.
Properties, and Therapeutic Efficacy in Psychoses. Drugs 1988; 35 [Initial results of a pharmacokinetic study of pipothiazine and its
(6): 670-84. palmitic ester (Piportil L4) in a schizophrenic population].
[25] Nayak RK, Doose DR, Nair NP. The bioavailability and Encephale 1984; 10: 171-6.
pharmacokinetics of oral and depot intramuscular haloperidol in [48] Schmidt K. Pipothiazine palmitate: a versatile, sustained-action
schizophrenic patients. J Clin Pharmacol 1987; 27: 144-150. neuroleptic in psychiatric practice. Curr Med Res Opin 1986; 10:
[26] Beresford R, Ward A. Haloperidol decanoate. A preliminary 326-9.
review of its pharmacodynamic and pharmacokinetic properties [49] Stauning JA, Kirk L, Joorgensen A. Comparison of serum levels
and therapeutic use in psychosis. Drugs 1987; 33(1): 31-49. after intramuscular injections of 2% and 10% cis(Z)-flupentixol
[27] Forsman A, Ohman R. Pharmacokinetic studies on haloperidol in decanoate in Viscoleo to schizophrenic patients. Psycho-
man. Curr Ther Res Clin Exp 1976; 20(3): 319-36. pharmacology (Berl) 1979; 65: 69-72.
[28] Chakraborty BS, Hubbard JW, Hawes EM, et al. Interconversion [50] Agrup-Andersson L, Bengtsson A, Erlandsson K, Gottfries
between haloperidol and reducedhaloperidol in healthy volunteers. CG, Witzell-Ostlund G. Flupenthixol decanoate. Controlled
Eur J Clin Pharmacol 1989; 37(1): 45-8. investigation concerning dosage. Acta Psychiatr Scand Suppl 1974;
[29] Cheng YF, Paalzow LK. Linear pharmacokinetics of haloperidol in 255: 7-14.
the rat. Biopharm Drug Dispos 1992; 13(1): 69-76. [51] McCreadie RG, Flanagan WL, McKnight J, Jorgensen A. High
[30] Llerena A, Alm C, Dahl ML, Ekqvist B, Bertilsson L. Haloperidol dose flupenthixol decanoate in chronic schizophrenia. Br J
disposition isdependent on debrisoquine hydroxylation phenotype. Psychiatry 1979; 135: 175-9.
Ther Drug Monit 1992; 14(2): 92-7. [52] Johnson DA, Ludlow JM, Street K, Taylor RD. Double-blind
[31] Kane JM, Davis JM, Schooler N, et al. A multidose study of comparison of half-dose and standard-dose flupenthixol decanoate
haloperidol decanoate in the maintenance treatment of in the maintenance treatment of stabilised out-patients with
schizophrenia. Am J Psychiatry 2002; 159: 554-60. schizophrenia. Br J Psychiatry 1987; 151: 634-8.
[32] Villeneuve A, Dogan K, Lachance R, Proulx C. A controlled study [53] Cookson IB. The effects of a 50% reduction of cis(z)-flupenthixol
of fluspirilene in chronic schizophrenia. Curr Ther Res Clin Exp decanoate in chronic schizophrenic patients maintained on a high
1970; 12(12): 819-27. dose regime. Int Clin Psychopharmacol 1987; 2: 141-9.
[33] Curry SH, Whelpton R, De Schepper PJ, Vranckx S, Schiff AA. [54] Aaes-Jorgensen T, Kirk L, Petersen E, Danneskiold-Samsøe P,
Kinetics of fluphenazine after fluphenazine dihydrochloride, Jørgensen A. serum concentrations of the isomers of clopenthixol
enanthate and decanoate administration to man. Br J Clin and a metabolite in patients given cis(Z)-clopenthixol decanoate in
Pharmacol 1979; 7: 325-31. viscoleo. Psychopharmacology (Berl) 1983; 81(1): 68-72.
[34] Ereshefsky L, Jann MW, Saklad SR, Davis CM, Richards AL, [55] Jørgensen A, Aaes-Jørgensen T, Gravem A, et al. Zuclopenthixol
Burch NR. Effects of smoking on fluphenazine clearance in decanoate in schizophrenia: serum levels and clinical state.
psychiatric inpatients. Biol Psychiatry 1985; 20: 329-32. Psychopharmacology (Berl) 1985; 87(3): 364-7.
[35] Wiles DH, Gelder MG. Plasma fluphenazine levels by [56] Poulsen JH, Olesen OV, Larsen NE. Fluctuation of serum
radioimmunoassay in schizophrenic patients treated with depot zuclopenthixol concentrations in patients treated with
injections of fluphenazine decanoate. Br J Clin Pharmacol 1979; 8: zuclopenthixol decanoate in viscoleo. Ther Drug Monit 1994; 16:
565-70. 155-9.
[36] Viala A, Hou N, Ba B, et al. Blood and plasma kinetics of cis(Z)- [57] Svendsen O, Blom L, Aaes-Jørgensen T, Larsen JJ. Local toxicity
clopenthixol and fluphenazine in psychiatric patients after of different drugs after intramuscular or intralipomatous injection
intramuscular injection of their decanoic esters. Psycho- in pigs: serumconcentrations after three different formulations of
pharmacology (Berl) 1984; 83: 147-50.
The Pharmacokinetics of Long-Acting Antipsychotic Medications Current Clinical Pharmacology, 2014, Vol. 9, No. 3 317

cis(Z)-clopenthixol. Acta Pharmacol Toxicol (Copenh) 1985; studies and population pharmacokinetic simulations. Annual
57(2): 78-87. Meeting of the American College of Neuropsychopharmacology,
[58] FDA: A study of ALKS 9072 in subjects with chronic stable Scottsdale, AZ, USA, Dec 7–11 2008. Poster no. 21
schizophrenia. http: //clinicaltrials.gov/ct2/show/NCT01493726. [61] Moller HJ. Long-acting injectable risperidone for the treatment of
Published December 12 2011. Accessed July 20, 2012. schizophrenia: clinical perspectives. Drugs 2007; 67: 1541-66.
[59] Hill CL, Phadke D, Boyce KM. Four-week iloperidone depot [62] Gefvert O, Eriksson B, Persson P, et al. Pharmacokinetics and
injectable: safety and pharmacokinetic profile in patients with D2 receptor occupancy of long-acting injectable risperidone
schizophrenia and schizoaffective disorder. Poster presented at: (Risperdal Consta™) in patients with schizophrenia. Int J Neuro-
161st annual meeting of the American Psychiatric Association; psychopharmacol 2005; 8: 27-36.
May 3-8, 2008; Washington, DC. [63] Bai YM, Ting CT, Chen JY, et al. Equivalent switching dose from
[60] Fleischhacker WW, Gopal S, Samtani MN, et al. Optimization of oral risperidone to risperidone long-acting injection: a 48-week
the dosingmstrategy for the long-acting injectable antipsychotic randomized, prospective, single-blind pharmacokinetic study. J
paliperidone palmitate: results of two randomized double-blind Clin Psychiatry 2007; 68: 1218-25.

Received: August 04, 2012 Revised: October 10, 2012 Accepted: December 14, 2012