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International Clinical Psychopharmacology:
doi: 10.1097/YIC.0b013e3283400d58
Original Articles

Evaluation of the effect of paliperidone extended release and quetiapine on corrected QT intervals: a randomized, double-blind, placebo-controlled study

Hough, David W.a; Natarajan, Jayaa; Vandebosch, Anb; Rossenu, Stefanb; Kramer, Michellea; Eerdekens, Mariëlleb

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Author Information

aJohnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, New Jersey, USA

bJohnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica N.V., Beerse, Belgium

Correspondence to Marielle Eerdekens, MD, Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, Beerse 2340, Belgium Tel: +32 14 60 6274; fax: +32 14 60 5089; e-mail: meerdeke@its.jnj.com

These data were presented at the Society of Biological Psychiatry (SOBP) 62nd Annual Meeting, May 19–24, San Diego, California, 2007; 160th American Psychiatric Association (APA) Annual Meeting, May 19–24, San Diego, California, 2007; 47th Annual Meeting of the National Institute of Mental Health, New Clinical Drug Evaluation Unit (NCDEU), June 14–17, Boca Raton, Florida, 2007; 59th Institute on Psychiatric Services (IPS), October 11–14, New Orleans, Louisiana, 2007; 20th Congress of the European College of Neuropsycho- pharmacology (ECNP), October 13–17, Vienna, 2007.

Received April 30, 2010

Accepted August 31, 2010

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Abstract

The effect of two atypical antipsychotics on QTc intervals (heart rate-corrected QT interval) was evaluated. Patients (N=109) with schizophrenia (79%) or schizoaffective disorder (21%) were randomly assigned in 2 : 2 : 1 ratio to paliperidone extended release (ER), quetiapine, or placebo. Doses of 12 and 18 mg/day of paliperidone ER were compared with quetiapine 800 mg/day. Least-squares mean change from baseline in population-specific linear-derived correction method from baseline to days 6–7 at individual tmax was 5.1 ms less [90% confidence interval: −9.2 to −0.9] with paliperidone ER 12 mg/day than with quetiapine 800 mg/day. On the basis of a prespecified 10-ms noninferiority margin, paliperidone ER was thus declared noninferior to quetiapine (primary analysis). Mean change in population-specific linear-derived correction method from baseline to days 11–12 at individual tmax was 2.3 ms less (90% confidence interval: −6.8 to 2.3) with paliperidone ER 18 mg/day than with quetiapine 800 mg/day. Treatment-emergent adverse events occurred in 36 (82%) patients treated with paliperidone ER, 41 (95%) patients treated with quetiapine, and 14 (64%) patients treated with placebo. No adverse events of a proarrhythmic nature were noted. The effect on the QTc interval in patients with schizophrenia or schizoaffective disorder was comparable between paliperidone ER 12 mg/day (maximum recommended dose), paliperidone ER 18 mg/day (supratherapeutic dose), and quetiapine 800 mg/day.

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Introduction

Abnormal prolongation or shortening in the QT interval, the period of time from the onset of ventricular depolarization to the end of ventricular repolarization, increases the risk of developing ventricular arrhythmias. Drug-induced alteration to the QT interval has become important in selecting a pharmacological treatment for patients with schizophrenia. Many antipsychotics increase the QT interval to various extents (Taylor, 2003; Harrigan et al., 2004; Stollberger et al., 2005), and case reports and epidemiologic studies have implicated antipsychotics as one of several factors involved in the increased cardiac-related mortality of patients with schizophrenia (Robbins et al., 2003; Taylor, 2003; Straus et al., 2004). In addition, there is natural diurnal variation in QT interval in healthy individuals (Bonnemeier et al., 2003). Thus, the immediate and prolonged release formulations of various antipsychotics may affect the QT interval differently.

Paliperidone extended release (ER) tablets [INVEGA; Janssen, LP, Titusville, New Jersey, USA; also marketed as prolonged release (PR) tablets in the European Union] have been approved in the European Union, the US, and many other regions of the world for the treatment of schizophrenia and schizoaffective disorder.

As part of the drug development program, studies were conducted to specifically evaluate the cardiovascular profile of paliperidone ER by using a thorough QT assessment. The first study (NCT00791349) in patients used an immediate release (IR) formulation of the compound, which produced modest but statistically significant increases in QTc intervals (heart rate-corrected QT interval) versus placebo. The IR paliperidone (8 mg) produced considerably higher plasma concentrations {mean Cmax [standard deviation (SD)]: 113 (43.3) ng/ml} on day 8 than did paliperidone ER at either the maximum recommended dose [12 mg/day; mean Cmax (SD)=34.6 (16.2) ng/ml after 6 days of dosing] or the supratherapeutic dose [18 mg/day; mean Cmax (SD)=54.0 (27.6) ng/ml after 4 days of dosing], following 6 days of dosing with 12 mg and 1 day of dosing with 15 mg).

The purpose of this study was to better understand the clinical relevance of the observations in the earlier thorough QT/QTc study of the IR formulation of paliperidone given the different pharmacokinetic (PK) characteristics of the ER formulation, to characterize the proarrhythmic potential, and to substantiate the cardiovascular safety profile of the currently marketed paliperidone ER. The primary assessment was to determine whether the effect on QTc for the highest marketed dose of paliperidone ER (12 mg) once daily was noninferior to the highest recommended dose of quetiapine (400 mg) (IR) administered twice daily at their individual tmax (both drugs at steady state). The second objective was to determine whether the effect on QTc for paliperidone ER (18 mg) given once daily (supratherapeutic dose) was noninferior to that of quetiapine (400 mg) administered twice daily at individual tmax.

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Methods

Patients

Men and women (age 18–50 years, inclusive), diagnosed with schizophrenia or schizoaffective disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 1994) with stable symptoms, were eligible. Minimum symptom stability, assessed by the investigator, included: no exacerbation of psychosis for at least 3 months before screening and a score of 4 (moderate) or less on the Clinical Global Impression Severity Score both at screening and the day prior to the start of the treatment phase (day −1). Patients were required to have normal 12-lead electrocardiograms (ECGs) at screening and days −1 and −2 (days prior to start of treatment phase) with: normal sinus rhythm, QTcB (correction using Bazett's method) not exceeding 430ms for men and 450ms for women, QRS interval less than 110ms, and PR interval less than 200 ms. Women were required to be postmenopausal for at least 2 years, to be surgically sterile, or to be utilizing birth control, and not pregnant.

Exclusion criteria included: meeting DSM-IV criteria for psychoactive substance dependence within 3 months preceding the study or at risk for suicidal or violent behavior, relevant history of a significant medical condition, including cardiovascular disease; clinically significant abnormal values on routine laboratory blood and urine testing; electrolyte abnormalities, such as hypokalemia, hypocalcemia or hypomagnesemia, within 5 days before randomization; the presence of any medical condition that could potentially alter the absorption, metabolism, or excretion of the study medication; ongoing treatment with any β-blocker, asthma medications, or insulin at the time of screening; known or suspected allergy, hypersensitivity, or intolerance to paliperidone ER, quetiapine, moxifloxacin, or any of the excipients; loss or donation of ≥500 ml of blood within 60 days before randomization; the use of any experimental drug or agent within 30 days, or within a period of less than five times the drug's half life, whichever is longer, before the first dose of study drug in the treatment phase; antidepressants (except selective serotonin reuptake inhibitors), lithium, mood stabilizers, or anticonvulsants within 2 weeks before randomization; and any long-acting injectable typical antipsychotic therapy within 8 weeks of screening, risperidone long-acting injectable (Risperdal CONSTA; Janssen, LP) within 100 days of screening, and paliperidone palmitate (INVEGA SUSTENNA; Janssen, LP, Titusville, New Jersey, USA) within 10 months before randomization, were prohibited.

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Study design

This was a multicenter, double-blind, randomized, active and placebo-controlled study conducted from 14 February 2006 to 20 June 2006 at 10 centers in the US. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and was consistent with Good Clinical Practices and applicable regulatory requirements. Patients provided written informed consent before entering the study.

The study consisted of three phases: a screening phase of up to 5 days, a placebo washout phase of up to 6 days, including 2 days of serial ECG measurements, and a treatment phase that included 1 day of open-label treatment with moxifloxacin (a fluoroquinolone antibiotic), 10 days of double-blind treatment, and end of study evaluations on day 12 or upon early termination (Fig. 1). On day 1 of the treatment phase, all patients received treatment with a single dose of moxifloxacin (400 mg), followed by multiple ECG measurements. Patients were then randomly assigned (2 : 2 : 1) to receive double-blind treatment with paliperidone ER, quetiapine, or placebo (days 2–11). A computerized randomization scheme was used, which was balanced using permuted blocks and implemented through a central call center.

Fig. 1
Fig. 1
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Patients randomly assigned to paliperidone ER were administered 12 mg/day once daily (the maximum recommended dose) on days 2–6, 15 mg/day on day 7, and 18 mg/day once daily (supratherapeutic dose) on days 8–11. Those assigned to quetiapine received 100 mg twice daily on day 2, 200 mg twice daily on day 3, 300 mg twice daily on day 4, and 400 mg twice daily (maximum recommended dose/day) on days 5–11. Paliperidone ER was supplied as 6 and 9 mg tablets, and quetiapine as 100 and 200 mg tablets. All active medication and matching placebo tablets were overencapsulated. Paliperidone ER was dosed once daily (two capsules of active medication in the morning and two capsules of placebo in the evening), quetiapine was dosed twice daily (in equally divided doses), and placebo-assigned patients received two capsules of placebo twice daily. The active medication and concurrent placebo were administered approximately 12 h apart, to maintain the study blind. To standardize the dosing relationship with respect to food intake, patients received the morning dose between 07 : 00 and 09 : 00 h, 30 min after having a standardized breakfast on days 2–11. The evening dose was administered between 19 : 00 and 21 : 00 h.

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Electrocardiogram measures

Serial time-matched 12-lead ECG triplicate readings were recorded on days −2 and −1 to establish the baseline population-specific linear-derived correction method (QTcLD) interval. Two days of measurements were taken to account for between day variation and diurnal variability in the QT interval. Serial time-matched 12-lead ECG triplicate readings were also recorded on day 1 (predose, 1, 1.5, 2.5, 3.5 h postdose), on days 6 and 11 (predose and 1, 1.5, 2.5, 3.5, 4.5, 6, and 12 h post dose), and on days 7 and 12 (23.5 h postdose of days 6 and 11, respectively) (Fig. 1).

Advanced automated ECG machines, with the capacity for digital signal processing, and validated for functionality within 12 months before day 1 of the treatment phase, were used. ECGs were recorded for 10 s to capture at least four regular heartbeats and the results of triplicate ECG readings were averaged to reduce variability (Fig. 1). All ECGs were read at a central laboratory by qualified cardiologists who were blinded to time, treatment, and patient identification. The ECGs were assigned on a random basis to the first available expert cardiologist (central reader). The inter-rater variability was established to be 0.5–0.7 ms for the QT interval readings.

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Safety measures

Safety assessments included treatment-emergent adverse event reports, clinical laboratory test results (hematology, serum chemistry, and urinalysis), vital signs, and physical examinations.

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Pharmacokinetic measures

Venous blood samples were taken on days −2, −1, 1, 6, 7, 11, and 12 to determine plasma concentrations corresponding to the timing schedule shown above for ECG recordings. The sponsor was responsible for these analyses.

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Sample size justification

A sample size of 40 patients per treatment group (paliperidone ER and quetiapine) was estimated to be sufficient to conclude noninferiority of paliperidone ER (12 mg/day) once daily to quetiapine (400 mg) twice daily at individual tmax with 81% power using an upper 1-sided 95% confidence interval (CI) and a noninferiority criterion of 10 ms, when the true difference in mean ΔQTcLD (changes from baseline in QT interval corrected for heart rate using the population-specific linear-derived correction method at individual tmax between paliperidone ER once daily and quetiapine twice daily) equals 2 ms and the SD equals 14 ms.

Moxifloxacin was included in the study for establishing assay sensitivity. Using an intrasubject SD of 11 ms and a 5% level of significance, 100 patients receiving moxifloxacin would be sufficient to detect an increase of 5 ms in ΔQTcLD between moxifloxacin and placebo baseline with 93% power.

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Statistical analyses

The QTcLD, calculated using linear regression between QT and RR, was the primary correction method used to correct the QT interval for measured heart rate. The linear-derived correction method was considered most appropriate as all drug-free QT/RR interval data of the study were incorporated in the linear modeling to derive the study-specific correction formula. Such correction typically yields the lowest correlation between QTc and RR. Two additional correction methods, Bazett (QTcB) and Fridericia (QTcF) were analyzed as secondary. Baseline at each scheduled time point was defined as the average of the readings from days −2 to −1 at the corresponding time point. The average of the readings from day −1 predose and day 1 predose were used for calculating the baseline for 23.5 h scheduled time point. QTc intervals and ΔQTcLD were summarized using descriptive statistics (mean, SD) at each scheduled time point.

The relationship between mean changes from baseline QTcLD against the corresponding mean drug concentration was explored graphically. SAS Version 9.1 (SAS Institute, Inc., Cary, North Carolina, USA) was used for the data analyses; S-Plus Version 8.0 (TIBCO Spotfire; TIBCO Software Inc., Palo Alto, California, USA) was used to create the figures.

The primary hypothesis was that the effect of paliperidone ER (12 mg/day) on ΔQTcLD was noninferior to that of quetiapine (400 mg) twice daily, both evaluated at steady state. An analysis of variance model was fitted to days 6–7 ΔQTcLD at individual tmax from the paliperidone ER (12 mg/day) once daily and quetiapine twice daily groups with treatment as a factor. Using the estimated least-squares (LS) means and intersubject variance obtained from the model, the two-sided 90% CI for the difference in means between paliperidone ER (12 mg) once daily and quetiapine (400 mg) twice daily was constructed. Noninferiority of paliperidone ER 12 mg once daily was concluded if the upper limit of the two-sided 90% CI (corresponding to an upper one-sided 95% CI) fell below 10 ms.

To evaluate paliperidone ER (18 mg) once daily versus quetiapine (400 mg) twice daily, the difference in mean ΔQTcLD at individual tmax and the associated two-sided 90% CI were estimated. To explore the effect of paliperidone ER (12 mg) once daily, paliperidone ER (18 mg) once daily, and quetiapine (400 mg) twice daily on days 6–7 and 11–12 versus concurrent placebo, ΔQTcLD data at individual tmax were selected in the active treatment group and ΔQTcLD data at observed median tmax (of the drug in the comparison) were selected in the placebo group. Using these data, the difference in ΔQTcLD between the active treatment group and concurrent placebo and associated 90% CI were estimated on days 6–7 and 11–12.

To evaluate assay sensitivity, a mixed-effect analysis of variance model was fitted to the QTcLD data from moxifloxacin (day 1) and placebo (at baseline) and treatment-by-scheduled time point as fixed effects and patient as random effect. Using the estimated LS means and intersubject variance obtained from the model, two-sided 90% CIs for the difference in means between moxifloxacin and placebo (at baseline) were constructed at each time point. Assay sensitivity was established if the lower limit of the two-sided 90% CI (corresponding to a lower one-sided 95% CI) fell above 0 ms, at one or more time points.

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Patient populations analyzed

The primary ‘per protocol’ pharmacodynamic analysis set included all randomly assigned patients who received double-blind study medication, completed all study evaluations until day 7 (predose), and did not deviate from the protocol. The secondary ‘per protocol’ pharmacodynamic analysis set included all randomly assigned patients who received double-blind study medication and completed all study evaluations until day 12. The safety analysis set included all patients who were randomized and received at least one dose of study drug during the double-blind period. The PK analysis set included all patients with available plasma samples.

The primary pharmacodynamic analysis set was used to test the primary hypothesis, to explore the effects of paliperidone ER (12 mg) once daily and quetiapine (400 mg) twice daily on days 6–7 versus concurrent placebo, and to establish assay sensitivity. The secondary pharmacodynamic analysis set was used to evaluate the cardiovascular safety of paliperidone ER (18 mg) once daily and quetiapine (400 mg) twice daily on days 11–12 versus concurrent placebo. The safety analysis set was used to evaluate all other pharmacodynamic and safety data.

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Results

Patient disposition and populations

Of the 130 patients screened, 110 were randomly assigned to treatment. One patient treated with moxifloxacin was discontinued before double-blind dosing on day 2, resulting in 109 patients for the safety analysis set. The primary pharmacodynamic analysis set (n=96) included 39 paliperidone ER, 37 quetiapine, and 20 placebo-treated patients. The secondary pharmacodynamic analysis set (n=91) included 35 paliperidone ER, 36 quetiapine, and 20 placebo-treated patients. Of the patients included in the pharmacodynamic analysis sets, three patients were completely or partly excluded from the actual analysis: two of these were excluded for aberrant concentration–time profiles (one quetiapine-treated patient was excluded from day 6 analyses and one paliperidone ER-treated patient was excluded on days 6 and 11, a third patient randomly assigned to quetiapine was also excluded on day 6 because of vomiting). PK analysis was performed with all available plasma samples from randomized patients. The patient population was predominantly black (n=68, 62%), men (n=78, 72%), with a mean age of 37 years (range: 18–51 years).

The treatment groups were generally well matched with respect to baseline demographics and psychiatric history in the safety analysis set (Table 1). A history of cardiovascular abnormality existed in 39 patients (36%), which was similarly distributed between treatments: n=17 (39%) in paliperidone ER, n=14 (33%) in quetiapine, and n=8 (36%) in placebo. Consistent with exclusion criteria, none of these patients had a relevant history of any significant or unstable cardiovascular disease. Demographic and baseline characteristics were consistent between the safety and pharmacodynamic analysis sets. In the paliperidone ER group, more patients (n=8, 18%) discontinued the study early compared with the quetiapine (n=5, 12%) or placebo (n=2, 9%) groups (Fig. 1). Withdrawal rates as a result of adverse events were similar and low across active-treatment groups (Fig. 1). In total, 100 (92%) patients received antipsychotic therapy before the study entry: of those 40 were in the paliperidone ER group, 38 were in the quetiapine group, and 22 in the placebo group.

Table 1
Table 1
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The most commonly administered concomitant medications during treatment (days 1–12) included: lorazepam (77%), zolpidem (72%), ibuprofen (29%), paracetamol (28%), aluminum hydroxide combined with magnesium hydroxide (11%), and benztropine (10%).

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Pharmacodynamic assessments
Assay sensitivity

Mean QTcLD values increased after administering moxifloxacin (400 mg) twice daily compared with baseline (placebo). The LS mean difference in QTcLD between moxifloxacin and placebo at baseline ranged from 4.1 ms (90% CI: 2.7–5.5) 1 h after dosing to 7.1 ms (90% CI: 5.7–8.5) at 3 h 30 min after dosing. At each scheduled time point, the lower limit of the two-sided 90% CI was above 0 ms, confirming assay sensitivity (Fig. 2).

Fig. 2
Fig. 2
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QTc intervals

At steady state, the LS mean ΔQTcLD at individual tmax was 1.1 ms for paliperidone ER (12 mg) once daily and 6.1 ms for quetiapine (400 mg) twice daily (days 6–7). The LS mean difference in ΔQTcLD at individual tmax between paliperidone ER (12 mg) once daily and quetiapine (400 mg) twice daily (days 6–7) was therefore estimated to be −5.1 ms (90% CI: −9.2 to −0.9) (Table 2). As the upper limit of the two-sided 90% CI did not exceed the prespecified criterion of 10 ms, noninferiority of paliperidone ER (12 mg) once daily to quetiapine (400 mg) twice daily was established. Similarly, ΔQTcLD at days 11–12 at individual tmax for paliperidone ER (18 mg/day) once -daily was 2.3 ms lower (90% CI: −6.8 to 2.3) than quetiapine (800 mg/day) twice daily (3.7 vs. 6.0 ms) signifying noninferiority of a supratherapeutic dose of paliperidone ER to quetiapine (Table 2; Fig. 3a and b). The ΔQTcLD at each scheduled time point and individual tmax were increased for paliperidone ER (both doses) and quetiapine (all days) compared with placebo (Fig. 3a and b). Similar results were obtained with QTcF. After correction with Bazett's method, QT and RR were still correlated (data not shown). As it is a well-known fact that Bazett's correction method results in substantial bias, QTcB results were not further discussed.

Table 2
Table 2
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Fig. 3
Fig. 3
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Categorical analysis

No patients in any treatment group had a treatment-emergent increase in QTcLD greater than 60 ms. A total of five patients had at least one 30–60 ms increase in QTcLD: two patients in each of the active treatment groups and one patient in the placebo group. No patients in any treatment group had a QTcLD interval greater than 480 ms at any time point. One woman in the paliperidone ER (18 mg) group had at least one observation of a QTcLD interval greater than 450 ms on days 11–12.

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Pharmacokinetic and pharmacodynamic relationships

On the basis of visual inspection of individual data scatterplots (not shown), no apparent relationship was visible between paliperidone plasma concentrations and ΔQTcLD. Figure 4 presents the mean ΔQTcLD versus mean drug plasma concentration for the four different groups [placebo, paliperidone ER 12 mg (day 6), paliperidone ER 18 mg (day 11), and quetiapine 400 mg twice daily (days 5–11)] at each time point measured.

Fig. 4
Fig. 4
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Safety

The overall incidence of TEAEs was higher for patients who received active treatment compared with those who received placebo (Table 3). The adverse events with highest incidence were somnolence and headache (23% each) in the total paliperidone ER group and somnolence (35%) and dry mouth (30%) in the quetiapine group (Table 3). The majority of adverse events were mild in severity. No deaths occurred during the study. Serious adverse events occurred in three patients: intermittent vertigo in one placebo-treated patient, increased psychosis after study completion in one patient each in the paliperidone ER and quetiapine groups. There were no clinically significant cardiovascular events or adverse events reported that suggested proarrhythmic potential. At least one incidence of orthostatic hypotension based on vital sign measurements occurred in five (11%) paliperidone ER-treated patients and 13 (30%) quetiapine-treated patients. Of these, orthostatic hypotension was recorded as an adverse event in three of the 13 patients treated with quetiapine and none of the five patients treated with paliperidone ER.

Table 3
Table 3
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Discussion

Although there has been no clear cause and effect relationship established (Taylor, 2003; Glassman, 2005; Lindstrom et al., 2005), QTc is still considered the best available predictor of drug-induced risk for dysrhythmia and sudden death (Reilly et al., 2000; Taylor, 2003; Kowey and Yan, 2005). Drug-induced mean change in QTcLD above 5 ms compared with drug-free baseline measurements in a defined patient population is one factor considered suggestive of a drug's proarrhythmic potential (Shah, 2005).

To date, paliperidone ER has been shown to be tolerable in both acute and long-term treatment of schizophrenia at the recommended once daily dose of 6 and 12 mg (Marder et al., 2006; Davidson et al., 2007; Kane et al., 2007; Kramer et al., 2007). This study was specifically designed and powered to evaluate the effect of paliperidone ER, the formulation that is now marketed, at the recommended dose (INVEGA Prescribing Information, 2008), on ventricular repolarization. Quetiapine, the active comparator, is from the same therapeutic class as paliperidone and is considered to have a good cardiovascular safety profile (Dev and Raniwalla, 2000; Tariot et al., 2000) with limited effects on cardiac electrophysiology (Taylor, 2003; Harrigan et al., 2004).

In this study, both paliperidone ER and quetiapine caused modest increases in the QTc interval. However, both the 12 mg/day (maximum recommended) and 18 mg/day (supratherapeutic) doses of paliperidone ER were noninferior to quetiapine 400 mg twice daily (maximum recommended dose) on mean change in QTcLD.

Moxifloxacin was administered to assess the sensitivity of the study population to a drug known to prolong the QT interval. The results indicate that the included population was sensitive to change given that the observed effect with moxifloxacin on the QT interval was comparable with that reported elsewhere (Avelox Prescribing information). Moxifloxacin was not administered as a concurrent control throughout the study, and thus the consistency of its actual effect throughout the study is not known. However, the increase in ΔQTcLD at individual tmax with quetiapine seen in this study is also consistent with results from earlier clinical trials that assessed effects of quetiapine on QTc prolongation (Arvanitis et al., 1997; Harrigan et al., 2004), which provides additional support to the validity of this study's outcome.

A QT interval greater than 500 ms in an individual patient is considered the threshold for clinical concern (Welch and Chue, 2000; Malik and Camm, 2001). In this study, none of the patients in any treatment group had a QTcLD interval greater than 480 ms at any time point, and only one patient (on paliperidone ER 18 mg once daily) had at least one observation of a QTcLD greater than 450 ms. These QTc findings regarding the effect of paliperidone ER on QT interval are also consistent with those from larger phase-3 studies during which frequent ECG sampling took place (Marder et al., 2006; Davidson et al., 2007; Kane et al., 2007; Kramer et al., 2007; Meltzer et al., 2008).

No patient treated with paliperidone ER experienced clinically significant cardiovascular events or adverse events that suggested proarrhythmic potential. Overall, reports of adverse events were consistent with reports from longer-term trials of paliperidone ER and no new safety signals were observed (INVEGA Prescribing Information, 2008).

Affected patients with schizophrenia or schizoaffective disorder are often treated with multiple medications that may prolong QTc, including psychotropic agents (e.g. tricyclic antidepressants, venlafaxine, antipsychotics, lithium) and medications commonly used for medical illnesses (e.g. many antibiotics, antihistamines, and antiarrhythmic medications) (Glassman and Bigger, 2001). Drug–drug interactions mediated by the cytochrome P450 system may lead to higher plasma concentrations than anticipated resulting in greater prolongations of the QTc. Although paliperidone ER has limited hepatic metabolism compared with other antipsychotics (Berwaerts et al., 2007; Spina and de Leon, 2007; Fowler et al., 2008; Urichuk et al., 2008), its use should still be avoided in combination with other drugs known to prolong QTc.

Many clinical factors, such as bradycardia, obesity, electrolyte abnormalities, or diabetes mellitus can also increase the predisposition of a patient to experience QT prolongation (Crouch et al., 2003). These factors should be considered before administration of any antipsychotic.

As quetiapine requires a slow titration (Seroquel US Package Insert), maximum blood levels may not have been reached at comparable time points to paliperidone ER, which does not require titration (INVEGA Prescribing Information, 2008). Thus, the doses may not have been therapeutically equivalent at early time points in the study. The degree to which the results of this study can be generalized to women or elderly patients is limited, as the study predominately consisted of middle-aged men. In addition, only 35% of patients had a history of cardiovascular abnormality. Those patients with significant or unstable cardiovascular disease were excluded resulting in limited data in this population.

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Conclusion

Paliperidone ER treatment increased QTc intervals to a similar degree as quetiapine. The results of this study, together with the data available from paliperidone ER clinical studies during which QT intervals were closely monitored, support the cardiovascular tolerability of paliperidone ER at the maximum recommended dose of 12 mg/day.

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Acknowledgements

The authors would like to thank Dr Balasubramanian Ramanathan (SIRO Clinpharm Pvt. Ltd.) and Dr Wendy P. Battisti (Johnson & Johnson Pharmaceutical Research & Development, L.L.C) for writing & editorial assistance. Bart Remmerie (Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium) provided additional scientific and technical review of the PK data for the manuscript. The authors also recognize Bhavna Solanki and Shean-Sheng Wang for their contribution with the statistical analysis.

The study investigators included: Beckett, Louise, MD; Brown, David, MD; Goenjian, Armen, MD; Hassman, Howard, DO; Litman, Robert, MD; Paniccia, Gregory, MD; Valencerina, Madeleine, MD; Volk, Stephen, MD; Walling, David, PhD; and Weissberg, Edward, MD, all from sites in the US.

This study was supported by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Drs Hough, Natarajan and Kramer are employed by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Raritan, NJ, USA. Drs Vandebosch and Eerdekens are employed by Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica N.V., Beerse, Belgium. Dr Rossenu was employed by Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica N.V., Beerse, Belgium at the time of this study.

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antipsychotics; arrhythmia; electrocardiogram; paliperidone; population-specific linear-derived correction method; quetiapine; QT/corrected QT interval; schizophrenia

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