Changes in plasma concentrations of risperidone and 9-hydroxyrisperidone and the associated clinical effects during the switch from oral risperidone to extended-release paliperidone tablets in patients with schizophrenia

Abstract

This study aimed to investigate changes in plasma concentrations of risperidone and 9-hydroxy-risperidone (9-OHR) and the associated clinical effects when switching from oral risperidone to extended-release (ER) paliperidone in patients with schizophrenia. This study included 25 patients with schizophrenia. Following a one-week screening period with a stable dose of risperidone, a six-week open-label switch study from risperidone to extended-release paliperidone (paliperidone ER) was conducted. Efficacy and safety assessments were performed on Day 1 and at Weeks 1, 2, 4, and 6. Plasma levels of the active fractions of oral risperidone and paliperidone ER were measured on Day 1 and at Week 1, respectively. Plasma levels of the active moiety (risperidone plus 9-OHR) while taking risperidone (mean dose: 4.0 mg) were significantly higher than plasma levels of 9-OHR while taking 6 mg of paliperidone ER. For 12 subjects taking only 3 mg of risperidone, plasma concentrations of the active moiety of risperidone were also significantly higher than those of 9-OHR while taking 6 mg of paliperidone ER. The amount of reduction in plasma levels was correlated with a temporal deterioration of clinical symptoms. These findings suggest that for patients with schizophrenia taking 3 mg or more of risperidone, an initial switching dose of 6 mg of paliperidone ER may be relatively low in terms of subsequent plasma concentrations and the associated clinical response.

Keywords

Paliperidone 9-hydroxy-risperidone risperidone schizophrenia switching dose

Introduction

Risperidone is an atypical antipsychotic drug with potent antagonistic properties for both dopamine D2 and serotonin (5-HT)2 receptors (Janssen et al., 1988; Leysen et al., 1988). This drug has proven therapeutic effects on both positive and negative symptoms of schizophrenia (Carman et al., 1995; Marder and Meibach, 1994).

Risperidone is primarily metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6) into an active metabolite, 9-hydroxy-risperidone (9-OHR), which is also known as paliperidone (Megens et al., 1994). Risperidone and its principal metabolite form an active serum compound termed the ‘active moiety’ (De Leon et al., 2010). Although some authors have stated that risperidone may be more potent and toxic than 9-OHR (De Leon et al., 2008), this metabolite exhibits a similar central nervous system (CNS) receptor occupancy profile to risperidone, and it is presumably equally effective (Van Beijsterveldt et al., 1994).

Based on this hypothesis, an extended-release formulation of paliperidone made using osmotic controlled-release system (OROS^®) technology (Janssen Pharmaceuticals, Inc., Vacaville, California, USA) is now commercially available as a new antipsychotic treatment option. This delivery profile allows treatment to be initiated with therapeutically effective doses without the need for initial dose escalation to allow for acceptable tolerability (Kramer et al., 2007; Marder and Meibach, 1994). The administration of extended-release paliperidone (paliperidone ER) results in small peak-to-trough fluctuations of 9-OHR plasma concentrations over 24 h in a steady state (De Leon et al., 2010). This avoids the rapid rise and fall of drug concentrations that are characteristic of immediate-release (IR) oral formulations. Because 9-OHR does not undergo significant hepatic metabolism (Vermeir et al., 2008), it is well tolerated by patients with poor hepatic function and is not susceptible to metabolic drug interactions.

In fact, a post-hoc analysis pooled from three six-week, double-blind, placebo-controlled trials revealed that 198 patients who exhibited an incomplete clinical response to risperidone treatment and were then administered paliperidone ER achieved clinical benefits, displayed good tolerability, and had low rates of discontinuation owing to adverse events (AEs) (Canuso et al., 2008). Another open-labeled, naturalistic, switching study with the subjects who had been treated with risperidone (mean dose: 5.9 (1.9SD) mg/day) also revealed general improvements on psychopathology, cognition, global functioning, extrapyramidal tolerability and attitude towards treatment after 12 weeks of treatment with paliperidone ER (mean dose: 9.1 (2.4SD) mg/day) (Cavallaro et al., 2012). Moreover, two longer-term switching studies demonstrated that clinical benefits shown in short-term switching trials were maintained after six or 12 months of treatment (Kim et al., 2013; Schreiner et al., 2010). Notably, both studies showed significant reduction on extrapyramidal symptoms. Due to these theoretical and clinical benefits, paliperidone ER may be an optimal alternative choice when a switch from risperidone is needed for various reasons.

In regards to dose correspondence between risperidone and paliperidone ER, Arakawa et al. (2008) demonstrated that the effective dose 50 (ED50) for dopamine D2 receptor occupancy following paliperidone ER treatment was 2.38 mg/day in the striatum and 2.84 mg/day in the temporal cortex. Other studies have found that the striatal ED50 of risperidone is 1.2 mg/day (Nyberg et al., 1999), and the limbic-cortical ED50 is 1.46 mg/day (Yasuno et al., 2001). Taken together, these studies indicate that the equivalent ratio between risperidone and paliperidone ER for a daily dose seems to be about 1:2.

Berwaerts et al. (2009) reported that 12 mg paliperidone ER and 4 mg risperidone IR resulted in a similar total exposure to 9-OHR and that on Day 6, the pharmacologically active fraction of risperidone led to similar increases in serum prolactin concentrations. Turkoz et al. (2011) demonstrated that, in terms of efficacy, paliperidone ER at 6–12 mg/day was superior to risperidone at 2–4 mg/day but was not different from risperidone at 4–6 mg/day. The safety profile was not related to the dose difference between these two drugs but rather related to the drug itself. Thus, from a viewpoint of clinical responses, the proposed equivalent ratio between risperidone and paliperidone ER is approximately less than 1: 2 (i.e. between 1:2 to 1:3).

To our knowledge, no pharmacokinetic studies have compared mean plasma levels of risperidone and paliperidone ER and the associated clinical response within the same individuals with schizophrenia during the period of switching between these drugs. The purpose of this study was to prospectively measure the steady-state plasma levels of risperidone and paliperidone ER and to assess the associated clinical response and safety profiles.

Methods

Subjects

This study included outpatients and inpatients aged 18–65 years with a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR) criteria (American Psychiatric Association, 2000). Subjects were eligible for participation if they had been treated with risperidone for ≥4 weeks prior to study entry. Patients were to have a Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) total score of 60–120 points at screening and baseline.

Exclusion criteria included previous treatment with two or more antipsychotics (for more than one month each), previous treatment with clozapine (for more than one month), high levels of suicidality (a score ≥3 on the suicide item of the Beck Depression Inventory) (BDI; Beck et al., 1961) or aggression (a score ≥6 on the hostility item of the PANSS), poor cooperativeness due to severe psychotic symptoms, a history of severe drug sensitivity/allergy or unresponsiveness to risperidone, and clinically significant neurological or physical illnesses. Also excluded were women who were pregnant, likely to become pregnant, or lactating.

Study design

Following a one-week screening period with a stable dose of risperidone, a six-week open-label study of switching from oral risperidone to paliperidone ER was conducted. On Day 1, all patients began administration with 6 mg of paliperidone ER for one week. Following this introductory period, the dosage was freely adjusted on the day of scheduled visit, according to observations of clinical response and tolerability.

The concomitant use of benzodiazepines, hypnotics or anticholinergic medications was permitted throughout the study as clinically indicated. Use of other psychotropic drugs such as antipsychotics other than study drugs, lithium, anticonvulsants, antidepressants, and psychostimulants was not allowed.

Prior to entering the trial, patients were required to sign an informed consent according to procedures approved by the Institutional Review Board (IRB) of Kyungpook National University.

Clinical assessments

Patient assessments were performed on Day 1 and at Weeks 1, 2, 4, and 6 after switching to paliperidone ER. Efficacy of the medication was assessed using the Clinical Global Impressions-Severity/Improvement (CGI-S/I) scale (Guy, 1976) and the PANSS (Kay et al., 1987) at every visit. AEs and extrapyramidal symptoms were also assessed at each time point with the Udvalg für Kliniske Undersøgelser (UKU) Scale (Lingjaerde et al., 1987), the Simpson-Angus Scale (SAS; Simpson and Angus, 1970), and the Barnes Akathisia Scale (BAS; Barnes, 1989). Additionally, every patient received a thorough medical workup during the screening period including physical examination, measurement of vital signs and body weight, electrocardiogram (ECG), and laboratory studies (a complete blood count, urea and electrolyte levels, thyroid and liver functioning, lipid profiles, fasting glucose, and urine pregnancy test for females). Fasting prolactin levels were measured in the morning at baseline and at Week 6.

Blood sampling and analytical methods

During a one-week screening period, oral risperidone was administered once a day at 09:00 and was stable for at least seven days before the assay. Baseline blood samples for the determination of the trough concentrations of steady-state risperidone and 9-OHR, the active moieties, for oral risperidone were collected at 09:00 just prior to the first administration of paliperidone ER on Day 1.

Subsequently, oral risperidone was discontinued and 6 mg of paliperidone ER was initiated once a day at 09:00 throughout the first week. Blood samples for the determination of the trough concentrations of steady-state 9-OHR following 6 mg of paliperidone ER were collected at 09:00 just prior to the administration of paliperidone ER on Day 8.

To determine the plasma concentrations of risperidone and paliperidone, serial blood samples were collected into tubes containing sodium heparin (Vacutainer; BD BioSciences, Franklin Lakes, New Jersey, USA) and centrifuged at 3000 rpm for 10 min. Plasma samples were then transferred to microcentrifuge tubes and stored frozen at −70°C until analyzed by the Clinical Trial Center at Kyungpook National University Hospital (KNUH; Daegu, Korea).

Plasma concentrations of risperidone and 9-OHR were analyzed by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) using an Agilent 1200 series HPLC system (Agilent Technologies, Inc.; Santa Clara, California, USA) coupled to an API 5000 mass spectrometer (ABSciex; Framingham, Massachusetts, USA). The analytes were separated using an Agilent Zorbax Eclipse XDB-CN column (100×2.1 mm internal diameter (i.d.), 3.5 µm particle size). A 60:40 (v/v) mixture of acetonitrile and ammonium formate buffer (2 mM, pH 3.69) was used in isocratic mode as the mobile phase, which was delivered at a flow rate of 0.2 mL/min. Mass spectrometric data-acquisition run times were 6 min, and quantitation was performed using the following MRM transitions: m/z 411.5 → 191.1 for risperidone and m/z 427.2 → 207.1 for paliperidone.

Analysis of risperidone concentrations

Following the addition of 1.4 mL of ethyl acetate to 100 µL of plasma in aliquots, 10 µL of methyl risperidone (10 ng/mL), the internal standard, was added. The mixture was vortexed for 5 min and then centrifuged at 13,200 rpm for 5 min. The supernatant (1.2 mL) was transferred to an Eppendorf tube and evaporated to dryness for 80 min at 45°C using a 2010 SpeedVac vacuum evaporator (Savant Instruments; Holbrook, New York, USA). The dry residue was reconstituted in 200 µL of mobile phase, and a 5 µL aliquot of this solution was injected for analysis.

Analysis of paliperidone concentrations

Following the addition of 390 μL of acetonitrile to 100 µL of plasma in aliquots, 10 µL of methyl risperidone (100 ng/mL) was added. The mixture was vortexed for 5 min and then centrifuged at 13,200 rpm for 5 min. The supernatant (25 µL) was transferred to an Eppendorf tube, and 475 µL of mobile phase was added. The resulting solution was filtered through a 0.22 µm nylon filter (Spin-X; Corning, New York, USA) into glass vials, and a 5 µL aliquot of this solution was injected for analysis. Linear calibration curves were established at 0.1–5 ng/mL for risperidone and 5–50 ng/mL for paliperidone (r=0.99 and r=0.99, respectively). The coefficients of variation for assay precision were ≤11.9% for risperidone, and ≤10.0% for paliperidone. The accuracy was ≥89.2% for risperidone and ≥92.1% for paliperidone. The lower limits of quantifications were 0.1 ng/mL for risperidone and 5 ng/mL for paliperidone.

Statistical analysis

Results are expressed as mean (standard deviation (SD)). Plasma concentrations of risperidone and 9-OHR compared between the two phases with a paired t-test (two-tailed) or Wilcoxon’s signed rank test, as appropriate, after normality testing. Scores measuring clinical efficacy and tolerability were also compared using paired t-tests. Relationships between plasma concentration and clinical measures were analyzed using Pearson’s correlation analyses. All the data were analyzed using SPSS for Windows, version 20.0 (SPSS, Inc.; Chicago, Illinois, USA). Differences were considered statistically significant at p<0.05.

Results

Subjects

This study included 25 patients (M:F = 15:10) with schizophrenia. The mean age of the subjects was 30.6 (8.2) years and the mean duration of illness was 2.4 (3.3) years. Twenty-one (84%) subjects were inpatients who were hospitalized with acute exacerbation of schizophrenia and four (16%) subjects were outpatients. The mean total PANSS and CGI-S baseline scores were 101.9 (29.0) and 5.0 (1.0), respectively. The demographic and baseline characteristics are presented in Table 1.

Table 1.

Demographic and baseline characteristics of patients with schizophrenia (mean±standard deviation (SD)).

Characteristic	Value
Male/female, n (%)	15(60)/10(40)
Age, years	30.6±8.2
Education, years	13.1±1.6
Height, cm	168.8±9.9
Weight, kg	62.3±14.6
BMI, kg/m²	21.5±4.1
CGI-S	5.0±1.0
PANSS
Positive	25.2±6.6
Negative	27.4±11.1
General	49.3±13.5
Total	101.9±29.0
Duration of illness, years	2.4±3.3
Dose of risperidone prior to paliperidone, mg/day	4.0±1.2

BMI: body mass index; CGI-S: Clinical Global Impression-Severity; PANSS: Positive and Negative Syndrome Scale.

All patients completed blood samples for drug concentrations on Day 1 and at Week 1. During the subsequent follow up period, a total of six patients dropped out, two at Week 2, three at week 4, and one at Week 6. The reasons for premature discontinuation included lack of efficacy (one subject), AEs (one subject), and loss to follow-up (four subjects).

Oral dose and plasma concentrations of risperidone versus paliperidone ER

During the one-week screening period, a stable dose of risperidone (mean dose: 4.0 (1.2) mg/day) was maintained. Following the switch to paliperidone ER, each patient was administered 6 mg of paliperidone ER throughout the first week, and then the dose was freely adjusted until the study endpoint at Week 6 (mean dose: 9.6 (2.6) mg/day). The mean ratio of paliperidone ER to risperidone (final dose of paliperidone ER divided by prior dose of risperidone) was 2.5 (0.7).

Paired t-test analyses revealed that when patients were ingesting a mean dose of 4.0 mg of risperidone, plasma levels of the active moiety (risperidone plus 9-OHR) were significantly higher than plasma levels of 9-OHR while taking 6 mg of paliperidone ER (19.7 (7.6) ng/mL vs 15.9 (7.1) ng/mL, respectively; t=4.7, p<0.001). While taking risperidone, plasma concentrations of active compound were 2.9 (3.2) ng/mL for risperidone and 16.8 (6.3) ng/mL for 9-OHR (Figure 1). The risperidone/9-OHR ratio in this study was 0.18 (0.21).

Figure 1.

Plasma concentrations of oral risperidone (RIS) versus extended-release paliperidone (paliperidone ER).

A Wilcoxon’s signed-rank test revealed that, even for patients taking 3 mg of risperidone (n=12), the plasma concentration of the active moiety was significantly higher than that of 9-OHR while receiving 6 mg of paliperidone ER (16.4 (4.0) ng/mL vs 14.1 (4.7) ng/mL; z= −3.06, p=0.002). There was a positive correlation between the dose of risperidone taken before the switch in medication and the reduction in concentration of the active moiety from Day 1 to Week 1 (r= −0.65, p<0.001; Figure 2) such that a higher dose of drug led to a larger reduction in moiety concentration.

Figure 2.

Relationship between prior dose of risperidone and concentration difference between oral risperidone (RIS) and extended release paliperidone (paliperidone ER).

Clinical efficacy

In general, significant clinical improvements in the PANSS total score were observed during the assessment period (Figure 3). Paired t-test revealed a significant reduction from Day 1 to Week 6 in the mean PANSS total score (score reduction=34.3 (30.5), t=4.89, p<0.001). More specifically, significant reductions were observed in positive symptoms (score reduction=10.1 (7.6), t=5.76, p<0.001), negative symptoms (score reduction=9.0 (10.7), t=3.66, p=0.002), and general psychopathologies (score reduction=15.2 (13.6), t=4.87, p<0.001). In parallel with PANSS score reduction, the CGI-S score was also reduced from ‘markedly ill’ (4.8 (1.1)) at baseline to ‘mildly ill’ (2.9 (1.2)) at Week 6 (t=4.26, p<0.001).

Figure 3.

Clinical improvement on the Positive and Negative Syndrome Scale (PANSS) total and subscale scores over time.

Relationship between plasma concentration and clinical measures

CGI-I scores at Week 2 were negatively correlated with difference in the concentration of activity moiety between risperidone at Day 1 and paliperidone ER at Week 1 (r= −0.61, p=0.002; Figure 4). In other words, the larger the reduction in drug concentration at these two time points was, the more the patients suffered temporal deterioration in the first week after switching to paliperidone ER. The negative relationship between improvement on the PANSS total score between Week 1 and Week 2 and the reduction in concentration was also significant (r= −0.58, p=0.004).

Figure 4.

Relationship between the concentration reduction during switch and Clinical Global Impression-Improvement (CGI-I) scale at week 2.

Tolerability

In terms of tolerability, only one patient taking 12 mg of paliperidone ER dropped out due to significant AEs consisting of extrapyramidal symptoms. There was no difference between the scores of the SAS as well as the BAS at Day 1 and those at Week 6 (2.7 (7.4) vs 1.5 (5.4), t=1.5, p=0.14 for SAS; 1.5 (2.0) vs 0.4 (1.4), t=2.3, p=0.08 for BAS).

Serum prolactin levels were measured at baseline and Week 6 among 19 patients (10 men, 9 women). Mean prolactin levels remained high between two time points among men (79.8 (32.6) ng/mL vs 72.8 (32.0) ng/mL, t=2.1, p=0.07) as well as women (200.9 (129.3) ng/mL vs 233.7 (115.7) ng/mL, t= −1.3, p=0.25).

Discussion

In this study, the steady-state plasma concentrations of risperidone, 9-OHR, and their sum (the active moiety) while taking risperidone (mean dose: 4.0 (1.2) mg) were 2.9 (3.2) ng/mL, 16.8 (6.3) ng/mL, and 19.7 (7.6) ng/mL respectively. These findings were on the lower end of the recommended plasma concentration of 20–60 ng/mL for the active moiety (Baumann et al., 2004) and were consistent with previous pharmacokinetic studies using similar doses of risperidone (Bondolfi et al., 2002; Spina et al., 2001). In addition, the plasma risperidone/9-OHR ratio in this study was, on average, in the range of approximately 0.1–0.2 (De Leon et al., 2010).

On the other hand, the steady-state plasma concentration of 9-OHR after taking 6 mg of paliperidone ER for one week was 15.9 (7.1) ng/mL in the same subjects. A previous multicenter retrospective analysis of therapeutic drug monitoring (TDM) data reported a mean paliperidone serum concentration of 35.7 (25.2) ng/mL (range 0–213 ng/mL; 25th–75th percentiles 19.5–46.0 ng/mL) with the mean daily dose of 7.8 (2.9) mg of paliperidone ER (Nazirizadeh et al., 2010). Similar to this multicenter study, the plasma level of 9-OHR in the current study seems to be on the lower end of the reported range.

In comparison, the present study revealed that the steady-state plasma level of 9-OHR while taking 6 mg of paliperidone ER was significantly lower than that of the active moiety while taking risperidone (mean dose: 4 mg) in patients with schizophrenia whose medication was changed from risperidone to paliperidone ER. Moreover, in 12 subjects who had taken 3 mg of risperidone prior to the switch, the concentration of 9-OHR while taking 6 mg of paliperidone ER did not reach levels similar to that of active moiety. In fact, all 12 patients in this study exhibited reduced concentration of active compounds after switching to 6 mg of paliperidone ER. As expected, the discrepancy between drug concentrations in the blood before and after the switch of medications was greater when the dose of risperidone used before the switch was higher.

More importantly, the reduction in the concentration was correlated with the temporal deterioration in clinical symptoms at Week 2. We assumed that this delayed effect may be partially due to delayed onset of action of antipsychotics including paliperidone ER. That is, though doses of paliperidone ER were increased at Week 1 and might reach previous concentration while taking risperidone, it would take some time to show evident efficacy with additional paliperidone ER. In effect, paliperidone ER begins to show significant clinical improvements at least from four days after administration when compared with placebo (Davidson et al., 2007; Marder et al., 2007) and the mean time to first improvement is 7.1 (4.1) days for oral risperidone (Zedkova et al., 2011). Another possible explanation is that the dose increment at Week 1 may still not have been enough to attain previous plasma levels of oral risperidone. In fact, among the 19 patients who completed this study, 14 patients (74%) increased the dose of paliperidone ER to 9 mg or 12 mg by the end of the study. Taken together, these findings indicate that, from the perspective of drug concentration, 6 mg of paliperidone ER as an initial switching dose seems low when patient has taken at least 3 mg or more of risperidone. That is, a 1:2 equivalent ratio between risperidone and paliperidone ER of the daily dose that was proposed from D2 receptor occupancy studies seems large (Arakawa et al., 2008; Nyberg et al. 1999; Yasuno et al., 2001) In this study, the mean ratio of paliperidone ER to risperidone (final dose of paliperidone ER divided by prior dose of risperidone) was 1:2.5. The current observations regarding plasma concentration rather support the proposed ratios from other clinical studies (i.e. between 1:2 to 1:3) (Berwaerts et al., 2009; Turkoz et al., 2011).

In terms of efficacy, patients showed a greater improvement after switching from risperidone to paliperidone ER, with a reduction of 34.3 (30.5) in the total PANSS score, which was evident in positive, negative, and general symptoms. The symptom reduction score in this study seemed greater than the −14.1(19.9) score in one previous pooled analysis from three six-week trials. Here, it was assumed that the superior outcomes may be due to the characteristics of the current subjects, who were younger, had shorter illness duration, and experienced uninterrupted use of antipsychotics during the study period. It should be noted that in order to obtain clinical improvements, the initial 6 mg dose of paliperidone ER was increased to an average of approximately 10 mg by the end of the study. In terms of tolerability, the extrapyramidal side effects were generally mild and tolerable, and no statistical differences were found in the severity of extrapyramidal symptoms between risperidone and paliperidone ER.

The most important clinical message is that conversion from oral risperidone to paliperidone ER requires care. This study is a good example to demonstrate potential disadvantages on ‘stop and start’ switching strategy, especially when the initial switching dose of paliperidone ER is relatively lower than the prior dose of oral risperidone. Thus, as in switching between other antipsychotics, cross-titration with careful dose adjustment is highly recommended in terms of efficacy and tolerability.

This study has several limitations. First, a relatively small sample size taking different doses of oral risperidone before the switch to paliperidone ER did not allow for a detailed analysis of equivalent dosage. In the same context, interpretations on clinical meaning and implications of this study should be more careful and limited. Future studies with larger population and various dose switching regimens are needed. Second, the direct switching strategy used in this study should be considered when interpreting the present results, as they may be different with the gradual cross-titration commonly used in a real–world clinical setting.

In conclusion, these findings suggest that, for patients with schizophrenia taking 3 mg or more of risperidone, 6 mg of paliperidone ER as an initial switching dose may be relatively low in terms of plasma concentration and associated clinical responses. Thus, a higher dose of paliperidone ER may need to be considered in such patients when switching medications.

Footnotes

Conflict of interest

The authors declare that there are no conflict of interest.

Funding

This work was supported by grants from Biomedical Research Institute, Kyungpook National University Hospital (2013) and the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A070001).

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(2011) Onset of action of atypical and typical antipsychotics in the treatment of adolescent schizophrenic psychoses. Neuro Endocrinol Lett 32: 667–670.