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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).
LEncphale, 2005 ; 31 : 609-15, cahier 1
609
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
610
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.
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-
E. Mannaert et al.
12/0
24 6
16/10
45 10
23
3
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)
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
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
31,5
50 mg
30
35
25
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
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)
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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E. Mannaert et al.
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
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.
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.
8.
9.
10.
11.
12.
13.
14.
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