Pharmacokinetics and tolerability of long-acting risperidone in schizophrenia

Schizophrenia Research 70 (2004) 91 – 100 www.elsevier.com/locate/schres

Pharmacokinetics and tolerability of long-acting risperidone in schizophrenia Marie¨lle Eerdekens *, Ilse Van Hove, Bart Remmerie, Erik Mannaert Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium Received 24 June 2003; accepted 15 November 2003 Available online 27 February 2004

Abstract The pharmacokinetics and tolerability of long-acting risperidone (Risperdal Constak) were evaluated in a multicenter, prospective, open-label, 15-week study of 86 patients with schizophrenia. Subjects stabilized on 2, 4 or 6 mg of oral risperidone once daily for at least 4 weeks were assigned to receive i.m. injections of 25, 50 or 75 mg of risperidone, respectively, every 2 weeks for 10 weeks. The 90% confidence intervals for the i.m./oral ratios of the mean steady-state plasma-AUC, corrected for dosing interval, and of the average plasma concentration of the active moiety (risperidone plus 9-hydroxyrisperidone) were within the range of 80 – 125%, indicating bioequivalence of the i.m. and oral formulations. However, mean steady-state peak concentrations of the active moiety were 25 – 32% lower with i.m. than oral dosing ( P < 0.05) and fluctuations in plasma activemoiety levels were 32 – 42% lower with the i.m. than oral regimen. Symptoms of schizophrenia continued to improve after switching from oral to i.m. dosing. Long-acting risperidone was well tolerated locally and systematically. Although overall bioequivalence of the two formulations was established, the differences in pharmacokinetic profiles between the two formulations indicate potential benefits for long-acting risperidone. D 2004 Elsevier B.V. All rights reserved. Keywords: Long-acting risperidone; Pharmacokinetics; Schizophrenia

1. Introduction An intramuscular (i.m.) formulation of risperidone (Risperdal Constak) has been developed to address the need for a long-acting formulation of an atypical antipsychotic. Long-acting risperidone is an aqueous suspension that contains the drug in a matrix of glycolic acid – lactate copolymer. Gradual hydrolysis of the copolymer at the site of injection ensures the slow but * Corresponding author. Tel.: +32-14-60-62-74; fax: +32-14-60 50-89. E-mail address: [email protected] (M. Eerdekens). 0920-9964/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2003.11.001

steady release of risperidone over a period of several weeks. Single-dose studies of the long-acting risperidone formulation have demonstrated that, starting at about week 3 after the injection, plasma levels of the active moiety (risperidone plus its active metabolite 9hydroxyrisperidone) gradually increase, peak at 4 –5 weeks and last approximately until 7 weeks (data on file, Janssen Pharmaceutica) (Fig. 1). The latent period before plasma active-moiety levels start to increase necessitates supplementation with oral risperidone during the first 3 – 4 weeks after the first injection. Steady-state bioavailability studies provide a more accurate indication of intra- and interindividual var-

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Fig. 1. Mean plasma levels of risperidone plus 9-hydroxyrisperidone after a single dose of 25 mg of long-acting risperidone in 14 patients with schizophrenia.

iability at therapeutic doses than do single-dose studies (Ereshefsky et al., 1986). Comparisons of oral and long-acting i.m. formulations of conventional agents, such as fluphenazine and haloperidol, have demonstrated that, when steady-state levels are achieved, the variability in the range of plasma concentration at a given i.m. dose is lower than with oral therapy (Tavcar et al., 2000). The reason for this is that the long-acting i.m. formulations offer the combined benefit of a more controlled and constant input rate together with the circumvention of firstpass metabolism (Ereshefsky et al., 1984). Thus, a more predictable plasma concentration profile may be anticipated with the long-acting i.m. preparation of risperidone than with oral formulations. In the present 15-week study, we compared the steady-state bioavailability of risperidone and the active moiety after oral and i.m. administration in patients with stable schizophrenia.

2. Method An international, multicenter, prospective, 15week, open-label study of long-acting risperidone was conducted in 86 patients with schizophrenia. The study protocol was reviewed by an independent ethics committee at each institution where the study was conducted and the study was performed in accordance with the Declaration of Helsinki and its subsequent revisions. All subjects provided informed consent after having been informed about the nature

and purpose of the study, participation and termination conditions, and risks and benefits. 2.1. Subjects Subjects were eligible for study inclusion if they were aged 18 – 65 years and had a diagnosis of schizophrenia of any subtype according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). A few subjects were subsequently rediagnosed as having schizoaffective or schizophreniform disorder. Exclusion criteria included a diagnosis of alcohol or substance abuse; a drug allergy or hypersensitivity to psychotropic drugs; a history of neuroleptic malignant syndrome or tardive dyskinesia; administration of a depot antipsychotic within one treatment cycle prior to study entry; the use of medications known to be hepatic enzyme inducers or inhibitors fewer than 2 weeks before study entry; or participation in an investigational drug trial for 30 days. Pregnant or lactating women were also excluded. 2.2. Dosing Single-dose data (Fig. 1) indicated that repeated administration of 25, 50 and 75 mg of long-acting risperidone every 2 weeks would provide plasma levels of the active moiety within the steady-state plasma concentration range observed after oral administration of 2, 4 and 6 mg of risperidone, respectively. Thus, subjects stabilized on 2, 4 or 6

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mg/day of oral risperidone for at least 4 weeks were assigned to receive i.m. injections of 25, 50 or 75 mg of long-acting risperidone, respectively, every 2 weeks. Based on simulations combining the singledose profile of long-acting risperidone with oncedaily oral risperidone, the following oral supplementation regimen was used to ensure a smooth transition: oral risperidone was to be continued at the same dose for the first 3 weeks, i.e., for 1 week before the first injection and for 2 weeks after the first injection, then halved for the next 2 weeks, and then discontinued. Risperidone was injected at the beginning of study weeks 2, 4, 6, 8 and 10, with injections alternating between the right and left gluteal muscles. The dosing scheme is shown in Table 1. 2.3. Assessments of bioavailability Venous blood samples (6 ml) were drawn from an antecubital vein for pharmacokinetic assessments according to the following schedule: Day 1: immediately before the morning oral dose; Day 7: immediately before the morning oral dose and at 1, 2, 3, 4, 6, 8 and 12 h after the morning dose; Day 8: immediately before the first i.m. dose (i.e., 24 h after the morning oral dose on day 7) and at 12 h after the i.m. dose;

Table 1 Risperidone administration scheme 4+ weeks prestudy Study weeks and study week 1 2 – 3a

Study weeks 4–5

Study weeks 6 – 16b

25-mg risperidone group 2 mg/day oral 2 mg/day oralc 1 mg/day oralc No oral 25 mg of long-acting risperidone every 2 weeks 50-mg risperidone group 4 mg/day oral 4 mg/day oralc 2 mg/day oralc No oral 50 mg of long-acting risperidone every 2 weeks 75-mg risperidone group 6 mg/day oral 6 mg/day oralc 3 mg/day oralc No oral 75 mg of long-acting risperidone every 2 weeks a

First injection on day 8. Last injection on day 64. c No intake on the day of i.m. injection. b

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Day 15: immediately before the morning oral dose; Day 22: immediately before the second i.m. dose (i.e., 24 h after the morning oral dose on day 21); Day 29: immediately before the morning oral dose; Days 36, 50 and 64: immediately before the third, fourth and fifth i.m. dose. DAYS 65 – 78: daily; and on DAYS 85, 92, 99, and 106. Whenever possible, subjects were hospitalized on days 7, 8 and 9 to ensure administration of the oral medication on the morning of day 7 and of the i.m. injection on the morning of day 8 and to ensure that blood samples for analysis were taken at exactly the right time-points. Blood samples were collected in heparinized tubes and centrifuged for 10 min at 2500 rpm (1000
g) within 2 h after collection. Separated plasma was aspirated with a disposable pipette and transferred to 5-ml plastic tubes and stored at  20 jC. The pharmacokinetics of the active moiety risperidone and 9-hydroxyrisperidone were studied using two different radioimmunoassay (RIA) methods. The first RIA measured the sum of risperidone and 9hydroxyrisperidone with a quantification limit of 0.20 ng/ml. The second RIA specifically measured unchanged risperidone with a quantification limit of 0.10 ng/ml. The plasma concentrations of 9-hydroxyrisperidone were obtained as the difference between the values for the active moiety and unchanged risperidone. 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 risperidone yielded an overall accuracy ranging from 102.6% to 109.1% over the evaluated concentration range (0.10 –200 ng/ml). The values obtained for the overall precision (% coefficient of variation [%CV]) were lower than 15% in the same concentration range. The RIA procedure for the active moiety yielded an overall accuracy ranging from 95.7% to 109.8% over the evaluated concentration range (0.20 – 1000 ng/ml). The values obtained for the overall precision (%CV for individual results at each concentration level) were lower than 15% in the same concentration range. The pharmacokinetic measures were as follows: Cpredose = plasma concentration before the oral dose

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on day 7 or the i.m. injection on day 64; Cmin = minimal plasma concentration during the 24 h after the oral dose on day 7 or minimal plasma concentration during the 14 days after the fifth i.m. injection; tmin = time to reach Cmin; Cmax = peak plasma concentration after the oral dose on day 7 or after the fifth i.m. dose determined by visual inspection of the data; tmax = time to reach Cmax; C24h = plasma concentration 24 h after the oral dose on day 7; AUC24h = area under the plasma concentration –time curve from 0 to 24 h after the oral dose on day 7, calculated by linear trapezoidal summation; AUC14days = area under the plasma concentration – time curve during the 14-day i.m. dosing interval, calculated by linear trapezoidal summation. For oral treatment, AUC14days was calculated by multiplying AUC24h by a factor of 14; Cav = average plasma concentration calculated as AUC24h/24 for the oral treatment and as AUC14days/336 for the i.m. treatments; % fluctuation = 100
(Cmax  Cmin)/Cav. Based on the individual plasma concentration/time data and using the actual sampling times, pharmacokinetic values were calculated for the active moiety and unchanged risperidone. Ratios of Cmax/Cmin were calculated after the oral dose on day 7 and after the fifth i.m. dose. Ratios of i.m. to oral treatment were calculated for Cmin, Cmax and AUC14days. 2.4. Assessments of tolerability and efficacy At study entry, a physical examination was performed and the subject’s medical and psychiatric histories, blood pressure, heart rate and electrocardiogram were recorded. Blood samples were taken for evaluation of hematology and chemistries; a urine sample was taken for urinalysis (BioAnalytical Research, Ghent, Belgium). Severity of extrapyramidal symptoms was assessed by means of the Extrapyramidal Symptom Rating Scale (ESRS) (Chouinard et al., 1980). Possible symptom deterioration during treatment with i.m. risperidone was evaluated by means of the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) and the Clinical Global Impressions (CGI) scale (Guy, 1976). Clinical improvement was defined as a decrease from baseline of 20% or more on either the total PANSS or the PANSS-derived Brief Psychiatric Rating Scale (BPRS). The ESRS, PANSS and CGI were repeated

during weeks 2, 4, 6, 10, 16 and at the end of the trial. Adverse events were recorded at each visit. Urine and blood samples were taken during week 8 and at the end of the trial. Blood pressure was measured during weeks 2, 4, 6, 8, 10 – 12 and, together with a physical examination and electrocardiogram, at the end of the trial. Both the investigator and subject evaluated the injection site during weeks 2, 4, 6, 8 and 10. The investigator’s evaluation of redness, pain, swelling and induration immediately before and after the injection was scored on a four-point categorical scale (from 0 = absent to 3 = severe). The subject’s evaluation of pain with or at the site of injection immediately after each injection was scored on a four-point categorical scale (from 0 = no pain at all to 3 = unbearably painful). 2.5. Data analysis The primary tests of bioavailability were to determine whether the concentration range of the active moiety after risperidone injections was maintained within the concentration range after oral treatment by comparing the steady-state trough (Cmin) and peak concentrations (Cmax) between the oral and i.m. regimens in each treatment group. Descriptive statistics were calculated for the plasma concentrations at each sampling time and for the derived pharmacokinetic parameters. One-way analysis of variance (ANOVA) was performed to test achievement of steady-state during oral therapy (predose plasma concentrations on day 7 versus 24 h postdose plasma concentrations on day 8) and i.m. therapy (predose plasma concentrations on day 64 versus postdose plasma concentrations on day 78). The pharmacokinetic values Cmin, Cmax and Cav during the oral dosing interval on day 7 and during the fifth i.m. dosing interval were analyzed after log transformation and compared using an ANOVA model allowing for effects of subjects and treatment. Results are presented after back transformation to the original scale. Treatment ratios comparing i.m. and oral values with 90% confidence intervals were constructed for the logarithmically transformed AUC, corrected for dosing interval and for Cmin, Cmax and Cav using the mean squares error from the ANOVA and the least squares means. The 90% confidence

M. Eerdekens et al. / Schizophrenia Research 70 (2004) 91–100 Table 2 Background characteristics of subjects in the three treatment groups Long-acting risperidone

Men/women Age (mean F S.E. years) Diagnoses Schizophrenia Schizoaffective disorder Schizophreniform disorder Previous psychiatric Hospitalizations (mean F S.E.) Baseline PANSS total score (mean F S.E.)

25 mg (N = 24)

50 mg (N = 31)

75 mg (N = 28)

15/10 39.6 F 2.0

20/12 40.8 F 2.0

21/8 39.6 F 2.1

21 2

26 4

23 3

2

2

3

5.0 F 0.8

6.8 F 1.4

10.8 F 2.6

58.0 F 4.3

61.1 F 3.3

67.1 F 3.3

interval of the Cav ratio was evaluated to determine whether it fell within the conventional bioequivalence acceptance criteria of 80 – 125%. Additionally, the lower limit of the 90% confidence interval of the Cmin

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ratio was evaluated to determine whether it fell above 80% and the higher limit of the 90% confidence interval of the Cmax ratio was evaluated to determine whether it fell below 125%. Efficacy was evaluated by means of the PANSS and CGI and changes in PANSS and CGI scores from baseline to endpoint were analyzed with the Wilcoxon matched-pairs signed-ranks test.

3. Results Background characteristics of the 86 patients in the three groups were generally similar except that those receiving higher doses of risperidone tended to have more previous psychiatric hospitalizations and higher baseline PANSS scores (Table 2). Most subjects (51%) had a DSM-IV diagnosis of paranoid schizophrenia and had been hospitalized for a psychiatric disorder five or more times before enrolling in this study. Nine subjects were not included in the pharmacokinetic statistical analyses: four subjects withdrew

Fig. 2. Median plasma concentrations of the active moiety after oral dosing (days 1 – 35) and i.m. injections of long-acting risperidone on days 8, 22, 36, 50 and 64.

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Table 3 Mean F S.D. and (median) steady-state pharmacokinetics of the active moiety after oral and i.m. risperidone in the three treatment groups

Cmin (ng/ml) Oral dosing i.m. dosing Cmax (ng/ml) Oral dosing i.m. dosing

2 mg oral/ 25 mg i.m. (N = 21)

4 mg oral/ 50 mg i.m. (N = 31)

6 mg oral/ 75 mg i.m. (N = 26)

11.4 F 3.6 (11.1) 11.3 F 4.5 (9.8)

22.3 F 12.1 (18.1) 24.3 F 16.0 (17.9)

32.6 F 15.7 (29.1) 32.6 F 16.5 (30.1)

32.9 F 9.2 (32.8) 22.7 F 9.2 (19.2)

74.1 F 31.5 (67.2) 57.3 F 32.3 (45.5)

107.0 F 49.0 (101.0) 80.6 F 40.0 (77.2)

3.5 F 0.7 (3.5) 2.9 F 2.3 (2.1)

3.5 F 1.2 (3.4) 3.9 F 6.5 (2.0)

137 F 32 (129) 83 F 45 (71)

130 F 45 (121) 88 F 54 (66)

Cmax/Cmin (ng/ml) Oral dosing 3.0 F 0.8 (2.7) i.m. dosing 2.4 F 1.8 (1.8) % Fluctuation Oral dosing 118 F 33 (118) i.m. dosing 69 F 44 (56)

plasma exposure of the active moiety starts to decline and is expected to disappear completely by week 7 or 8 after the last injection. During both oral and i.m. risperidone administration, levels of the active moiety and of unchanged risperidone remained at steady state in all subjects. A dose-proportional increase ( P < 0.05, linear regression analyses) in steady-state Cmin and Cmax concentrations of the active moiety was noted after both oral and i.m. administration of risperidone. For example, the median Cmin of the active moiety increased from 11.1 to 18.1 to 29.1 ng/ml as the oral dose increased from 2 to 4 to 6 mg and from 9.8 to 17.9 to 30.1 ng/ml as the i.m. dose increased from 25 to 50 to 75 mg (Table 3). There was also a dose-proportional

before and three during the i.m. phase; one subject erroneously received a 25-mg injection instead of a 75-mg injection; and one subject had inconsistencies between time of plasma sampling indicated on the collection tubes and the case report form. 3.1. Bioavailability Median plasma levels of the active moiety (risperidone plus 9-hydroxyrisperidone) during oral dosing and after the five injections of long-acting risperidone are shown in Fig. 2. The data-rich plasma concentration – time profile on day 7 reflects a steady-state dosing interval for oral risperidone, while the data-rich profile between days 64 and 78 reflects a steady-state dosing interval for i.m. risperidone. As a result of the typical release profile of i.m. risperidone, the latter interval captures the main release phase of the third injection administered on day 36. The continued steady-state exposure beyond day 78 until day 99 reflects the main release phases of the fourth (day 50) and fifth (day 64) injection, respectively. Between days 99 and 106, i.e., 6 weeks after the last injection,

Fig. 3. Median steady-state trough (Cmin) and peak (Cmax) plasma concentrations of the active moiety after oral and i.m. dosing.

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Fig. 4. Percentage fluctuations in plasma active-moiety concentrations after oral and i.m. dosing.

increase ( P < 0.05, linear regression analyses) in steady-state Cpredose, Cav and AUC of the active moiety after both oral and i.m. administration. The mean steady-state Cmax concentrations of the active moiety were approximately 25 – 32% lower after long-acting risperidone than after oral risperidone ( P < 0.05, ANOVA), but the mean steady-state Cmin concentrations were not changed ( P>0.05, ANOVA). For example, the mean Cmax of the active moiety decreased from 32.9 to 22.7 ng/ml (31%) when 2 mg of oral risperidone was changed to 25 mg of i.m. risperidone, while the mean Cmin was 11.4 ng/ml after the oral dose and 11.3 ng/ml after the i.m. dose (Fig. 3). Fluctuations in plasma levels of the active moiety were substantially lower after i.m. injection (range,

Table 4 Bioavailability of the active moiety after oral and i.m. dosing: least squares means (log-transformed) and 90% confidence intervals (CI)

AUC14 days Oral dosing (ngh/ml) i.m. dosing (ngh/ml) i.m./oral ratio (%) 90% CI Cav Oral dosing (ng/ml) i.m. dosing (ng/ml)

2 mg oral/ 25 mg i.m.

4 mg oral/ 50 mg i.m.

6 mg oral/ 75 mg i.m.

5996 5303 88 81 – 97

12,027 11,571 96 89 – 104

18,056 16,886 94 85 – 102

17.8 15.8

35.8 34.4

53.7 50.3

56 – 71%) than after oral treatment (range, 118 – 129%) (Fig. 4). Bioequivalence in total body exposure (AUC14days) and the average concentration (Cav) during one dosing interval was achieved after oral and i.m. administration (Table 4). The 90% confidence intervals for the mean steady-state AUC14days and Cav ratios (i.m. to oral) were all within the bioequivalence range of 80 – 125% for the active moiety. The patients continued to receive oral risperidone during the first and second i.m. dosing cycles (full Table 5 Mean (F S.E.) ESRS scores in the three groups Long-acting risperidone 25 mg

50 mg

75 mg

N

Score

N

Score

N

Score

25 23 21 21

3.2 F 0.7 3.1 F 0.9 2.8 F 0.8 2.4 F 0.6

32 29 31 31

5.7 F 0.9 5.4 F 0.9 4.9 F 1.2 4.2 F 1.0

29 27 27 26

8.1 F 1.4 7.1 F 1.2 6.5 F 1.0 5.2 F 0.8

Patient questionnaireb Day 1 25 1.6 F 0.3 Day 8 23 1.5 F 0.3 Day 64 21 1.2 F 0.4 Day 106 21 1.0 F 0.3

32 29 31 31

3.0 F 0.6 2.8 F 0.6 2.4 F 0.6 2.2 F 0.6

29 27 26 26

4.2 F 0.6 3.8 F 0.6 3.6 F 0.7 3.2 F 0.6

a

ESRS total Day 1 Day 8 Day 64 Day 106

a

Parkinsonism + dystonia + dyskinesia total. Best score 0, worst score 102. b Best score 0, worst score 36.

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Table 6 Adverse events reported in three or more patients in any treatment group Long-acting risperidone

Influenza-like symptoms Insomnia Condition aggravated Anxiety Depression Headache Tachycardia Nervousness Injury Fatigue Agitation

25 mg (N = 25)

50 mg (N = 32)

75 mg (N = 29)

3 3 0 3 2 2 0 1 0 1 1

3 4 5 2 4 3 3 0 1 3 3

5 4 5 4 2 3 3 4 3 0 0

oral dose during cycle 1 and half dose during cycle 2). Trough and intermittent (1 week after the first and second i.m. injections) plasma active moiety levels during the first and second i.m. dosing cycles

were comparable to the steady-state trough levels observed at other time points, indicating sufficient oral supplementation during the latent period before initial release of risperidone from the long-acting formulation. 3.2. Tolerability and efficacy Severity of extrapyramidal symptoms (ESRS scores) was low at baseline, that is, after 4 or more weeks of treatment with oral risperidone, and was further reduced after the switch from oral to i.m. risperidone (Table 5). Adverse events were reported in 19 (76%) of the 25 patients in the 25-mg group, in 26 (81%) of the 32 patients in the 50-mg group, and in 22 (76%) of the 29 patients in the 75-mg group. Adverse events reported in three or more patients in any treatment group are shown in Table 6. Serious adverse events were reported in four patients; none were considered to be related to the trial treatment by the investigators.

Table 7 Mean (F S.E.) PANSS total, subscale and PANSS-derived BPRS scores at baseline and changes on day 8 (at the time of the first i.m. injection) and at endpoint Long-acting risperidone 25 mg

Total Baseline Day 8 Endpoint Positive symptoms Baseline Day 8 Endpoint Negative symptoms Baseline Day 8 Endpoint General psychopathology Baseline Day 8 Endpoint PANSS-derived BPRS Baseline Day 8 Endpoint

50 mg

75 mg

N

Score

N

Score

N

Score

24 23 23

58.0 F 4.3  1.3 F 0.8  4.6 F 1.6y

31 29 31

61.1 F 3.3  0.8 F 0.7  2.9 F 2.9

28 28 28

67.1 F 3.3  1.1 F 0.7  6.0 F 2.5*

24 23 23

12.0 F 1.3 0.3 F 0.3  0.3 F 0.6

31 29 31

11.2 F 0.8  0.1 F 0.3 0.2 F 0.6

28 28 28

14.2 F 0.9  0.6 F 0.3  1.8 F 0.9*

24 23 23

15.8 F 1.2  0.5 F 0.4  1.5 F 0.6

31 29 31

18.1 F 1.2  0.4 F 0.3  1.6 F 0.9

28 28 28

19.1 F 1.2 0.1 F 0.4  1.2 F 0.9

24 23 23

30.2 F 2.3  1.1 F 0.4  2.8 F 0.9y

31 29 31

31.8 F 1.9  0.3 F 0.4  1.5 F 1.8

28 28 28

33.8 F 1.7  0.6 F 0.3  3.0 F 1.3*

24 23 23

32.5 F 2.3  1.0 F 0.5  2.7 F 1.0*

31 29 31

33.5 F 1.7  0.3 F 0.4  0.8 F 1.6

28 28 28

38.2 F 2.0  1.0 F 0.4*  3.8 F 1.6*

* P < 0.05 versus baseline. y P < 0.01 (Wilcoxon matched-pairs signed-ranks test).

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No clinically relevant changes in vital signs or results of clinical laboratory tests were noted. According to the investigators’ evaluations, in most cases, no induration, pain, redness or swelling was noted at the injection site. Overall, no pain at the injection site was reported by more than 60% of the patients throughout the trial and fewer than 5% reported that an injection was ‘‘rather painful’’ (score of 2 on the four-point scale). Patients’ symptoms (PANSS total and subscale scores and scores on the PANSS-derived BPRS) showed few fluctuations during study weeks 1 – 5 while being switched from oral to i.m. risperidone or during the following weeks on i.m. dosing (Table 7, Fig. 5). Symptom severity was reduced at most time points and responses were similar in the three treatment groups. CGI severity scores showed minimal improvements or no changes during the study: mean ( F S.E.) changes from baseline to endpoint on the CGI severity scale were  0.5 F 0.1 (from 2.1 F 0.3 to 1.7 F 0.3) in the 25-mg group, 0.0 F 0.2 (1.8 F 0.2 at both time points) in the 50-mg group and  0.3 F 0.2 (from 2.5 F 0.2 to 2.2 F 0.2) in the 75-mg group (CGI scores range from 0 = not ill, 1 = very mild to 6 extremely severe). At the last i.m. injection on day 64 (at steadystate plasma levels), clinical improvement was noted in 44 –57% of patients in the three groups according to

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PANSS scores (20% or greater reduction) and in 52 – 62% according to PANSS-derived BPRS scores (20% or greater reduction).

4. Discussion and conclusions The primary purpose of the present study was to determine bioequivalence of i.m. and oral dosing. With respect to daily body exposure (plasma AUC), injections of 25, 50 or 75 mg of long-acting risperidone every 2 weeks were equivalent to daily oral doses of 2, 4 or 6 mg of risperidone, respectively. However, peak (Cmax) plasma active-moiety concentrations were 25 – 32% lower after long-acting risperidone than after oral risperidone, while trough (Cmin) concentrations did not differ between long-acting and oral risperidone (Fig. 3). The absence of the first-pass hepatic effect and the slow but steady release from the depot attenuated the fluctuations between peak and trough concentrations, as illustrated by a major reduction in percentage fluctuations with the long-acting formulation (Fig. 4). This could result in lower absolute doses of the long-acting formulation being as efficacious as higher reference oral doses, as has been observed with some depot formulations of

Fig. 5. Mean changes in PANSS total scores from baseline to endpoint.

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conventional neuroleptics (Nayak et al., 1987). This hypothesis cannot be confirmed from the data of the present study because of its limitations, which include the open-label design and administration of concurrent psychotropic medications to 66% of the patients. What can be concluded, however, is that patients with schizophrenia, schizoaffective disorder or schizophreniform disorder can be smoothly transitioned from oral to long-acting risperidone. The smooth plasma profile observed with longacting risperidone in this trial was associated with a decrease in ESRS total ratings and an excellent tolerability profile. Patients and investigators reported little or no injection-site pain or other adverse reaction. Conventional depot antipsychotics are often associated with pain, bleeding, hematoma and other injection-site reactions (Hay, 1995; Bloch et al., 2001) that may be related to the oil-based conventional depot injections. Water-based injections such as long-acting risperidone appear to be less painful than oil-based ones (Schou Olesen and Huttel, 1980). Symptoms of schizophrenia were not exacerbated and were even improved after switching from oral to i.m. therapy (Fig. 5), and at the last i.m. injection 44 – 62% of subjects showed clinical improvement from baseline, despite having been clinically stable for at least 4 weeks before the study began. The efficacy of long acting risperidone has also been demonstrated in the double-blind 12-week study of Kane et al. (2003) and the long-term study of Fleischhacker et al. (2003).

Acknowledgements This study was supported by Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium.

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