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PSYCHOPHARMACOLOGIE

Pharmacokinetic profile of long-acting injectable risperidone


at steady-state : comparison with oral administration
E. MANNAERT (1), A. VERMEULEN (1), B. REMMERIE (1), P. BOUHOURS (2), J.-C. LEVRON (1)

Rsum. La rispridone est un antipsychotique atypique


ayant une grande affinit pour les rcepteurs srotoninergiques 5HT2A et dopaminergiques D2. Une formule injectable
libration prolonge (LAI rispridone) a rcemment t
dveloppe en utilisant la technologie des microsphres. Les
molcules de rispridone sont encapsules dans des microsphres constitues dun copolymre biodgradable [poly-(d,
1lactide-co-glycolide)], dont la dgradation progressive libre
lentement le principe actif au site dinjection. La prsente
tude a eu pour objectif dvaluer le profil pharmacocintique
de la rispridone libration prolonge lquilibre des
concentrations plasmatiques (steady-state) lors de la simulation dun rgime dinjections rptes, comparativement au
profil pharmacocintique de la rispridone orale action
immdiate. Les profils des concentrations plasmatiques
lquilibre ont t simuls daprs les rsultats obtenus lors
dadministration de doses uniques des deux formes de rispridone, par voie orale et par voie intramusculaire (IM). Les
concentrations plasmatiques de la fraction active (rispridone inchange et 9-hydroxy-rispridone) ont t dtermines par radio-immuno-essai, pendant 72 heures aprs une
dose orale de 1 mg de rispridone chez 12 volontaires sains
et jusqu 84 jours aprs une injection IM. de 50 mg de rispridone libration prolonge chez 26 patients schizophrnes. Les rsultats ont t extrapols des rgimes
dadministration rpte de rispridone de 4 mg/jour par voie
orale et de 50 mg en IM toutes les deux semaines, en utilisant
le programme Win Nonlin. La comparaison des profils plasmatiques des deux modes dadministration, lorsque ltat
dquilibre est obtenu, a montr un pic plasmatique moins
lev (46 versus 62 ng/ml) et un moindre degr de fluctuations entre les concentrations maximum Cssmax et minimum
Cssmin (53 versus 145 %) avec la formulation injectable par
rapport la formulation orale. Les rsultats de ces simulations
ont t confirms lors dtudes effectues chez des patients
avec les deux formules, orale et injectable libration prolonge. En conclusion, le profil pharmacocintique simul de

la rispridone libration prolonge, injecte par voie IM toutes les deux semaines, a montr, ltat dquilibre, des
niveaux de concentrations plasmatiques compris dans lintervalle de ceux obtenus avec ladministration par voie orale de
doses quotidiennes quivalentes mais avec des fluctuations
de moindre amplitude et moins frquentes (1/14 jours versus
1/jour).
Mots cls : Antipsychotique ; tat dquilibre ; Pharmacocintique ;
Rispridone libration prolonge.

Summary. The single dose pharmacokinetic profiles of longacting injectable (LAI) risperidone and oral risperidone were
extrapolated to steady-state. Plasma concentrations of the
active moiety (unchanged risperidone + 9-hydroxy-risperidone) were measured by radioimmunoassay up to 72 h after
a single oral 1 mg dose of risperidone in healthy volunteers
(n = 12), and up to 84 days after a single intramuscular injection of 50 mg LAI risperidone in schizophrenic patients
(n = 26). These data were projected to multiple dose regimens (4 mg/day for the oral formulation and 50 mg every
2 weeks for LAI formulation) using the software package WinNonlin, and average steady-state pharmacokinetic profiles
were predicted. The most interesting results, obtained at
steady-state, were a lower predicted peak plasma level
(46 vs. 62 ng/ml) and a lower predicted degree of fluctuation
between Cssmax and Cssmin (53 vs 145%) with LAI compared
to oral administration, which is in line with actual steady state
data on LAI risperidone. In conclusion, the pharmacokinetic
profile of LAI risperidone administered every 2 weeks
ensures a steady-state profile with concentrations falling in
the interval observed with an equivalent oral dose but with
lower and less fluctuations (i.e. 1/2 weeks vs 1/day).
Key words : Antipsychotic ; Long-acting risperidone ; Pharmacokinetics ; Steady-state.

(1) Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340
Beerse, Belgium.
(2) Janssen-Cilag, Medical Affairs Psychiatry, 1, rue Camille Desmoulins, 92787 Issy les Moulineaux, France.
Travail reu le 16 mai 2005 et accept le 27 octobre 2005.
Tirs part : E. Mannaert ( ladresse ci-dessus).
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E. Mannaert et al.

INTRODUCTION
The importance of maintenance therapy in schizophrenia has been well established and long-term maintenance
treatment with antipsychotic medication appears critical in
preventing relapse (4, 6, 11).
Conventional depot antipsychotics have been developed
since the 1970s ; the outpatient treatment with these intramuscular formulations resulted in better compliance, a reduced hospital time and risk of rehospitalization, with significantly lower relapse rates than their oral equivalents (2, 5, 7).
However the depot preparations available have the
classical limitations associated with conventional antipsychotics, including notably a high incidence of extrapyramidal symptoms (EPS) and lack of effects on negative
symptoms.
Risperidone is an atypical antipsychotic that possesses
a high affinity for serotonergic 5HT2A and dopaminergic
D2 receptors, and its pharmacodynamic profile allows for
clinical efficacy in both positive and negative symptoms
with a lower risk of EPS and tardive dyskinesia (15, 16).
In order to associate the superiority of the atypical character of risperidone in controlling the negative and positive symptoms of schizophrenia and reducing the incidence of parkinsonian symptoms, with the advantages of
a long-duration formulation in reducing the risk of relapse,
a long-acting injectable (LAI) formulation of risperidone
has recently been developed (10, 13).
Long-acting risperidone is the first atypical antipsychotic
available as a long-acting injectable formulation. The intramuscular administration of LAI risperidone ensures continuous coverage for long-term stability and might help to
ensure long-term recovery, offering the benefits of an atypical antipsychotic together with ensured medication delivery.
Microsphere technology was used for the long-acting formulation of risperidone : risperidone has been encapsulated
in polymer microspheres of polylactide co-glycolide (PLG)
containing metabolic precursors of lactic acid and glycolic
acid. The PLG is a biodegradable medical-grade polymer,
commonly used in sutures and medical devices.
After intramuscular injection of the microspheres suspended in an aqueous diluent, the copolymer is gradually
hydrolysed and the microspheres progressively degrade,
ensuring the slow but steady release of risperidone over
several weeks.
Steady-state comparative pharmacokinetic studies,
performed with oral and long-acting formulations of conventional anti-psychotics, have demonstrated a lower
variability in plasma concentrations with long-acting formulations. A recent study conducted in schizophrenic patients
during 15 weeks has shown substantially lower fluctuations in plasma levels of the active moiety (i.e. sum of risperidone and its equipotent active metabolite 9-hydroxyrisperidone) after intramuscular injection of LAI than after
oral treatment of risperidone (8, 9, 20).
The objective of the present study was to simulate
repeated-dose pharmacokinetic profiles of LAI risperidone
by extrapolating from single-dose data, and to compare
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these simulated profiles to actual steady-state pharmacokinetics obtained with oral and LAI risperidone.

METHODS
Single dose pharmacokinetic data following administration of risperidone were obtained in healthy volunteers
(oral formulation) and in schizophrenic patients (longacting injectable formulation).
Trials were approved by local ethics committees and
performed in accordance with the declaration of Helsinki
and its subsequent revisions.
At the screening visit, the subjects gave their voluntary
written consent to participate in the trial after having first
been informed about the nature and purpose of the study,
participation and termination conditions, and risks and
benefits.
Subjects
Oral administration Healthy male subjects (n = 12)
aged 18-65 years were included. Before the trial, subjects
were phenotyped for their cytochrome P4502D6 metabolic
capacity, using the dextromethorphan test.
Intramuscular injection Subjects (n = 26) aged
18-65 years and having a diagnosis of schizophrenia or
any subtype according to the Diagnostic and Statistical
Manual Disorder (DSM IV) were eligible for the trial.
Exclusion criteria common to both groups, included
participation in an investigational drug trial within
30 days prior to the first visit, donation of blood within
the 60 days preceding the first visit, the use of medication known to be hepatic enzyme inducers or inhibitors
less than two weeks prior to the dose of trial medication,
diagnosis of alcohol or substance abuse, drug allergy
or hypersensitivity towards psychotropic drugs, including risperidone.
For schizophrenic patients, additional exclusion criteria
included treatment with depot neuroleptic formulations
within one treatment cycle prior to the trial start, history of
neuroleptic malignant syndrome, history of tardive dyskinesia, pregnancy or breast-feeding, and lack of adequate
contraception in female subjects of childbearing potential.
Medications
Oral administration Prior to treatment, subjects underwent an overnight fast of at least 10 hours.
An oral dose of 1 mg risperidone was administered with
200 ml of water, in the morning, using 0.5 ml of 2 mg/ml risperidone oral solution. Subjects remained fasting until
2 hours post-dose ; a lunch was served 5 hours post-dose.
Intramuscular injection Subjects received a single gluteal intramuscular injection of 50 mg of long-acting risperidone.

LEncphale, 2005 ; 31 : 609-15, cahier 1

During the trial, antipsychotics (except risperidone, clozapine, olanzapine, sertindole, quetiapine, or any of the
newly registered antipsychotics) could be administered to
the subjects at the investigators discretion.
Assessments
Blood sampling
Venous blood samples (6 to 8 ml) were taken from an
antecubital vein via an indwelling catheter according to the
following schedules :
oral administration just before dosing and at 8, 15,
30 min and at 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 48 and 72 hours
after drug administration ;
intramuscular injection immediately before injection and at 1, 2, 4, 8 hours on day 1 and daily sampling
on day 2 (24 h post-dose), day 3 (48 h post-dose), day 5
(96 h post-dose) and on days 8, 11, 15, 18, 22, 25, 29,
32, 36, 39, 43, 50, 57, 64, 72, 78 and 85 after treatment.
Blood samples were collected in heparinized tubes and
were centrifuged for 10 min at 2,500 rpm (1,000 xg).
Plasma was separated, transferred into 5 ml plastic tubes
and stored at 20 C.
Drug assay
The plasma concentrations of risperidone and active
moiety (risperidone plus 9-hydroxy-risperidone) were determined using two validated radioimmunoassay (RIA) procedures, reported earlier. One RIA method measured the sum
of risperidone and 9-hydroxy-risperidone, i.e., the active
moiety, directly on plasma. The other RIA method specifically
measured unchanged risperidone after extraction of plasma
samples. The limit of quantification (LOQ) was 0.10 ng/ml for
unchanged risperidone and 0.20 ng/ml for the active moiety.
The plasma concentrations of 9-hydroxy-risperidone were
calculated by subtracting the risperidone concentrations
from those of the active moiety. The accuracy and precision
of the assays were assessed by comparison with independently prepared quality control samples, spiked at different
concentrations throughout the calibration range. The RIA
procedure for unchanged risperidone yielded an overall
accuracy of 100.1% (n = 280) over the evaluated concentration range (0.10 40 ng/ml), which was extended up to
200 ng/ml after appropriate dilution of the samples. The overall precision (% CV) was 11.1% in the same concentration
range. The RIA procedure for the active moiety yielded an
overall accuracy of 94.8% (n = 212) over the evaluated concentration range (0.20 10 ng/ml), which was extended up
to 1,210 ng/ml after appropriate dilution of the samples. The
overall precision was 9.3% in the same concentration range.
Pharmacokinetic analysis
Based on individual plasma concentration-time data
obtained after single oral and intramuscular administra-

Pharmacokinetic profile of long-acting injectable risperidone at steady-state

tions, the following pharmacokinetic parameters were


measured : Cmax = peak plasma concentration determined by visual inspection of the data, tmax = time to reach
the peak plasma concentration, = elimination rate constant, determined by linear regression of the terminal part
of the log-linear concentration-time curve, AUC24h = area
under the plasma concentration-time curve from 0 to 24 h,
calculated by linear trapezoidal summation for the oral
solution, AUClast = area from 0 to the last quantifiable concentration for LAI formulation, AUC = area under the
plasma concentration-time curve extrapolated to infinity
using , and t1/2 term = apparent terminal half-life defined
as 0.693/.
Pharmacokinetic parameters were calculated for the
active moiety and for unchanged risperidone.
Simulation procedure
When an antipsychotic drug is administered on a chronic basis, plasma concentrations gradually build up over
time. This accumulation and the resulting repeated dose
profile depend on the drug dosing regimen, the route of
administration and the basic pharmacokinetic parameters
of the compound. Single dose profiles can be modelled
and used to simulate an equilibrium state ; this steadystate is obtained when the amount of drug delivered to
the systemic circulation is equal to the amount of drug
being eliminated from the body. As a general rule, more
than 90% of the steady-state plasma concentration is attained in a time approximately equal to four times the halflife of the drug, which is the case after oral administration
of risperidone. However, from its typical release profile,
showing a latent period of 3 weeks before plasma concentrations start to build up, the steady-state of LAI risperidone is reached after the 4th injection (day 60) (8).
Steady-state plasma levels of the active moiety, theoretically obtained after repeated administrations, were
simulated from the pharmacokinetic data measured after
single oral and intramuscular administrations, according
to the following regiments :
The mean active moiety concentration-time data
measured after 1 mg oral administration of risperidone
were recalculated for 2 and 4 mg doses, based on the dose
proportionality of risperidone, previously demonstrated
(1, 8, 17). During the first two days, the dose was 2 mg
once daily and from day 3 onwards, the dose was 4 mg
once daily. Simulated plasma levels are depicted, building
up to steady-state.
The mean active moiety concentration-time data
measured after a single intramuscular injection of the
50 mg long-acting risperidone dose were simulated to
steady-state, according to a frequency of injection of every
two weeks.
Simulations were performed using the pharmacokinetic
software package WinNonlin Enterprise (version 4.0.1a),
with the non-parametric superposition procedure. Nonparametric superposition is a generally applied technique
of projecting single-dose data to steady-state for drugs
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E. Mannaert et al.

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with linear pharmacokinetic properties ; the technique was


applied on mean data for oral and LAI risperidone, so
the steady-state projections are to be considered
means as well.
The pharmacokinetic parameters of the active moiety
obtained after simulation were as follows : Cssmax = peak
plasma concentration at steady-state, Cssmin = minimal
plasma concentration at steady-state, AUC24h = area
under the plasma concentration-time curve during the 24hour oral dosing interval at steady-state, AUC14d = area
under the plasma concentration-time curve during the 14day i.m. dosing interval at steady-state, Cssav = average
plasma concentration at steady-state, calculated as
AUC24h/24 for the oral administration and AUC14d/336 for
the intramuscular administration.
Assessment of tolerability
Safety was evaluated in schizophrenic subjects receiving a single injection of LAI risperidone. Physical examination, electrocardiogram, clinical laboratory tests including haematology, biochemistry and urinalysis, were
performed at screening and at the end of the trial. Heart
rate and blood pressure were measured at screening, just
before, at 4 hrs and 24 hrs and then every week after drug
administration.
Evaluations of the injection site were done by both the
investigator and the subject. The investigator evaluated
the site of injection for redness, pain, swelling and induration.
Extrapyramidal symptoms (EPS) were assessed by
means of the Extrapyramidal Symptom Rating Scale
(ESRS), at selection and at each emergent EPS. Adverse
events were recorded during the trial.
RESULTS
Subject characteristics are listed in Table I for the
twelve healthy volunteers and for the twenty-six schizo-

phrenic subjects. The dextromethorphan metabolic ratios


(MR) obtained in healthy subjects showed two CYP2D6
poor metabolizers (MR > 1), one intermediate (MR = 0.12)
and nine extensive metabolizers (MR between 0.00026
and 0.015). Schizophrenic patients that received the single LAI injection were not phenotyped with dextrometorphan, but based on the risperidone metabolic ratio, 9 out
of 26 subjects could be identified as CYP2D6 poor metabolizers (AUCRIS/AUCActive Moiety > 0.6).
TABLE I. Characteristics of subjects with single doses
of risperidone.
Oral dosing Intramuscular LAI
(n = 12)
(n = 26)
Men/Women
Age (mean SD, years)
Diagnoses
Schizophrenia
Schizoaffective disorder

12/0
24 6

16/10
45 10

23
3

Pharmacokinetics after single oral administration


The mean pharmacokinetic data of unchanged risperidone and active moiety, following oral and intramuscular
administrations are listed in Table II.
After oral administration, risperidone was rapidly absorbed with peak plasma concentrations attained within 0.5
to 1 h. Consistent with their metabolic phenotype (MR), the
values of risperidone AUC24h and t1/ 2term were higher in
2 poor (AUC24h : 123-271ng.h/ml, t1/2 term : 15-17 h)
and 1 intermediate (AUC24h : 49 ng.h/ml, t1/2term : 11 h)
metabolizers than in the 9 extensive metabolizers
(AUC24h : 31 18 ng.h/ml, t1/2 term : 2.8 0.5 h). However, for the active moiety, the pharmacokinetic parameters were similar between poor, intermediate and extensive metabolizers (Table II).

TABLE II. Pharmacokinetic parameters of risperidone and active moiety, after single oral and intramuscular administration
(mean SD).

Parameter

tmax (h)
Cmax (ng/ml)
AUC24h (ng.h/ml)
AUClast (ng.h/ml)
AUC (ng.h/ml)
t1/2 term (h)

Oral dosing (1 mg)


Risperidone
(n = 9)a
(n = 12)

0.8 0.3
7.9 2.9
31.3 17.5

32.0 18.4
2.8 0.5

1.0 0.7
9.1 4.1
60.4 72.9

75.4 107
5.7 5.5

Active moiety
(n = 12)

1.3 0.6
12.6 3.6
127 44

201 78
19.5 2.4

Intramuscular LAI (50 mg)


Risperidone
Active moiety
(n = 26)
(n = 17)b
(n = 26)

745 199
15.6 9.7

4,050 2,086
4,194 2,094
60.4 26.3

776 176
21.6 15.0

5,873 3,604
6,054 3,600
72.2 30.8

786 170
39.8 15.7

11,978 4,469
11,654 4,129
95.1 75.7

a. Excludes poor (n = 2, AUC24h = 123-271 ng.h/ml, t1/2 term = 15-17 h)) and intermediate (n = 1, AUC24h = 49 ng.h/ml, t1/2term = 11 h) metabolizers based on dextrometorphan phenotying.
b. Excludes patients with risperidone metabolic ratio (AUCRIS/AUCActMoiety) > 0.6.

612

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Pharmacokinetic profile of long-acting injectable risperidone at steady-state

Pharmacokinetics after single LAI formulation

Safety after single LAI formulation

After single-dose injection of 50 mg risperidone into the


gluteal muscle, the release profile of the active moiety,
depicted in figure 1, showed a small initial release within
the first 24 hours (< 1% of the administered dose), followed
by a lag time of about 3 weeks, during which very little drug
was released from the microspheres. Therapeutic plasma
concentrations were reached at 3 to 4 weeks after injection, were maintained for an additional 2 weeks (throughout 6 weeks after injection), and subsided by 7 weeks
after injection. Comparing the values of Cmax, AUC and
half-life between unchanged risperidone and the active
moiety (Table II), it appears that risperidone represents
about one third of the active moiety in extensive metabolizers, while the terminal half-lives are in the same order
of magnitude for both compounds (60 h vs. 95 h), whereas
after oral administration, risperidone only amounts to 15%
of the active moiety in extensive metabolizers, while its terminal half-life is much shorter than that of the active moiety
(2.8 h vs. 19.5 h). Although it is difficult to make firm conclusions on the relative contribution of risperidone to the
total active moiety based on this small cross-study comparison, the discrepancy in terminal half life is outspoken
and logical due to the particular pharmacokinetic behaviour of the LAI formulation. After intramuscular injection
of the long acting formulation, risperidone is slowly
released over a period of several weeks due to the gradual
hydrolysis of the copolymer at the site of injection. This
slow rate of absorption becomes the rate-limiting step
determining the pharmacokinetic profile. The rate of elimination thus essentially matches the rate of absorption
and the plasma half-life corresponds to the rate of absorption (flip-flop kinetics).

The majority of the reported adverse events were mild


or moderate in severity, and none of them were considered
potentially drug-related. The most commonly reported
adverse events were anxiety (n = 3), headache (n = 4),
influenza-like symptoms (n = 4), psychosis (n = 8), and
weight increase (n = 4). Two cases of severe psychosis
were considered as serious adverse events and they were
reported to be doubtfully (n = 1) and possibly (n = 1) drugrelated.
Few changes in laboratory safety parameters and
abnormalities during the physical examination were
observed, these were considered to be of no clinical relevance. No relevant increase in heart rate, no relevant
changes in ESRS assessment, body weight and ECG,
were observed. The LAI formulation was also locally well
tolerated.

31,5

50 mg
30

Active moiety conc. ng/ml]

Simulated steady-state plasma levels of the active


moiety (risperidone + 9-hydroxy-risperidone) for the oral
and LAI formulation are depicted in figure 2. Visual
observation of the curves shows that steady-state is
obtained after the fourth injection with the long-acting
formulation.
Comparison of plasma levels
60
Active moiety, ng/ml

35

25

Pharmacokinetics after simulation of repeated


administrations

50
40
30
20
10

PO

LAI

24,3

0
20,2

20

10,7

3,50

3,96

70

87

98

112

3,60
3,11

1,99
2,38

3,30
2,36

1,62

0,94
0,01 0,01 0,01 0,01

0
1

56

6,12
4,12
3,36

0,01

42

FIG. 2. Comparison of mean plasma levels of active moiety


of risperidone at steady-state, after oral dosing 4 mg/day (PO)
and LAI dosing 50 mg/2 weeks (LAI).

10

4,85 4,62

28

Time (days)

16,6

15

14

2 3 5 8 11 15 18 22 25 29 32 36 39 43 50 57 64 71 78 85

Time (days)

FIG. 1. Mean plasma concentration-time curve after single


Gluteal)Intramuscular injection of 50 mg LAI risperidone
in patients (n = 26).

The comparison of steady-state pharmacokinetic parameters of the active moiety (Table III) between oral dosing
(4 mg/day) and LAI dosing (50 mg/2 weeks) showed
lower values of Cmax, Cmax/Cmin ratio and % of fluctuation
with LAI formulation than with oral dosing, whereas the
mean steady-state plasma level, Cssav, was similar for the
two formulations.
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TABLE III. Pharmacokinetic parameters of the active moiety


at steady-state after simulation of repeated administrations
with oral and long acting formulations.
Parameter
Cssmax (ng/ml)
Cssmin (ng/ml)
Cssmax/Cssmin
Css av (ng/ml)
AUC (ng.h/ml)
% fluctuation

Oral dosing
(4 mg/day)

Intramuscular LAI
(50 mg/2 weeks)

62
17
3.6
30.8
740 1
145

46
27
1.7
35.4
11,908 2
53

1. AUC24h.
2. AUC14d.

DISCUSSION
The aim of this study was to assess the plasma concentration-time profile of the active moiety during chronic
treatment with long-acting injectable risperidone, in order
to compare its pharmacokinetic behaviour with that of the
oral formulation.
Simulation of plasma concentrations at steady-state
mimics a chronic treatment. Simulations were performed
using single dose data ; extrapolation from 1 mg to 4 mg
per day was supported by the dose proportional pharmacokinetics of risperidone, previously demonstrated in healthy volunteers and in patients (1, 8, 17) in a range from
0.5 to 8 mg b.i.d. Furthermore, the pharmacokinetics of risperidone are time-invariant, which justifies the linear
superposition of single-dose data to predict multiple-dose
exposure.
The most interesting result of this comparative study
was to reveal, at steady-state, the lower value of the peak
plasma concentration (46 vs. 62 ng/ml) and the lower
degree of fluctuation (53 vs. 145%) for the simulated PKprofiles after injection with 50 mg LAI formulation compared to the 4 mg oral solution. Based on the characteristic
linear behaviour of risperidone, the same lower peak level
and lower degree of fluctuation can be expected if one
would compare simulations with the 25 mg LAI formulation
with the 2 mg oral formulation. Simulated pharmacokinetic
profiles, obtained from separate pharmacokinetic studies
with single oral and LAI dosing, are in good agreement with
published actual steady-state pharmacokinetic results
obtained in patients switched from chronic oral risperidone
to chronic LAI risperidone formulation treatment (8). In this
study, schizophrenic subjects stabilized on 2, 4 or 6 mg
oral risperidone once daily were assigned to receive i.m.
injection of 25, 50 or 75 mg long-acting risperidone every
2 weeks for 10 weeks ; steady-state peak concentration
of the active moiety was 25-32% lower and fluctuation
32-42% lower with LAI formulation than with oral treatment. Moreover, the comparison (Table IV), at similar
doses, between the actual pharmacokinetic parameters,
obtained at steady-state in patients (8) and their simulated
values calculated in the present study, demonstrate the
614

very good predictability of these simulations, supporting


the pharmacokinetic linearity of risperidone and its active
moiety during chronic treatment. The gradual release of
risperidone after LAI administration can explain the noticeable decrease in the percentage of fluctuation between
peak and trough concentrations, as compared to the oral
solution.
TABLE IV. Comparison of pharmacokinetic parameters
at steady-state between chronic treatment in patients (8)
and simulated values.
Oral dosing
(4 mg/day)

i.m.LAI dosing
(50 mg/2 weeks)

Parameters
Eerdekens
Eerdekens
Simulations
Simulations
study
study
Cssmax (ng/ml)
Cssmin (ng/ml)
Css av (ng/ml)

74 31
22 12
36

62
17
31

57 32
24 16
34

46
27
35

1. Mean SD.

Atypical antipsychotics like risperidone have been


shown to be efficient against both positive and negative
symptoms of schizophrenia, and have a lower risk of inducing extrapyramidal symptoms (EPS) and tardive dyskinesias (3). Risperidone does not demonstrate obvious
relationships between plasma concentrations of the active
moiety and clinical improvement. In clinical trials using
high risperidone doses (15, 16), the highest doses were
associated with the highest occurrences of EPS but not
with greather efficacy. Several studies of D2 -receptor
occupancy, using positron-emission tomography (PET),
have been performed with risperidone (12, 14, 18, 19).
Results of these studies permitted estimation of the threshold D2-occupancy for antipsychotic action at 65% and for
higher risk of EPS at 80%. A recent study, performed in
patients with schizophrenia receiving 25, 50 or 75 mg of
long-acting risperidone for 10 weeks (12), showed that the
best antipsychotic response was seen with the 50 mg
dose, corresponding to D2-receptor occupancy in the
range of 70-80%, while the only EPS-like adverse event
was reported in the 75 mg group in which more than half
of the patients had D2-receptor occupancy > 80%. These
relationships between clinical efficacy, EPS risk and the
level of D2-receptor occupancy, underline the importance
of a long acting antipsychotic formulation that maintains
a sufficiently high trough plasma concentration to safeguard efficacy, while at the same time minimises the peak
plasma concentration to reduce the risk of developing
adverse events.

CONCLUSION
The present data confirm the anticipated linear pharmacokinetic behaviour of both oral an LAI risperidone, with
the repeated dose pharmacokinetics being well predicted
from single dose data using a simulation model.

LEncphale, 2005 ; 31 : 609-15, cahier 1

The pharmacokinetic profile of long-acting injectable


risperidone administered every 2 weeks, ensures a predictable steady-state plasma level within the intervals
observed with equivalent daily oral doses, but with much
lower fluctuations between Cssmin and Cssmax. Furthermore, these lower fluctuations occur once every two
weeks with the long-acting formulation while they appear
every day with the oral formulation. The lower peak plasma
levels and continuous coverage may lead to greater efficacy and safety over time, the optimal benefits being
achieved through repeated administration every 2 weeks.
Acknowledgements. The study was supporter by :
Johnson & Johnson Pharmaceutical Research & Development,
a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B2340 Beerse, Belgium.
Janssen-Cilag, Medical Affairs Psychiatry, 1, rue Camille Desmoulins, 92787 Issy les Moulineaux, France.

Pharmacokinetic profile of long-acting injectable risperidone at steady-state

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