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The ER formulation of paliperidone is expected to boost compliance and tolerability. Research suggests that paliperidone ER is both effective and well-tolerated, and further studies are eagerly awaited
Professor of Pharmacology *Pharmacology Section
Department of Clinical and Experimental
Medicine and Pharmacology
University of Messina IRCCS Centro Neurolesi Bonino-Pulejo Messina Italy
Schizophrenia is a severe mental illness that affects approximately 1% of the population. Schizophrenia is a heterogeneous disorder characterised by positive and negative symptoms and often associated with cognitive impairment and depressive symptoms.
The course of the illness is generally chronic, with relapses of psychotic episodes, cognitive reduction, social decline and poor quality of life. Antipsychotic medication is the primary intervention for the stabilisation of acute psychotic episodes and the prevention of symptom recurrence in patients with schizophrenia. Over the past decade “atypical” or “second-generation” antipsychotics such as clozapine, risperidone, olanzapine, quetiapine, sertindole, ziprasidone, aripiprazole and amisulpride have become the treatment of choice for schizophrenia due to the perception of a more favourable tolerability profile and a broader spectrum of activity as compared with “typical” or “first-generation” compounds. In general, these agents tend to be characterised by a low propensity to produce acute extrapyramidal symptoms and tardive dyskinesia and a weak potential to cause elevation of serum prolactin levels. On the other hand, treatment with some of these medications has been associated with substantial risk of metabolic effects, such as weight gain, hyperglycaemia and lipid dysregulation, and cerebrovascular adverse events, in particular stroke.[2,3]
Paliperidone (InvegaTM; Janssen) is a second-generation antipsychotic recently approved by the FDA and EMEA for the treatment of schizophrenia.[4–9] Chemically, paliperidone is 9-hydroxyrisperidone – the major active metabolite of risperidone, a well-established second-generation antipsychotic drug. This agent combines the efficacy of risperidone with an innovative delivery system that releases the drug at a controlled rate.
Paliperidone has been developed as an extendedrelease (ER) formulation that uses an osmotic controlled- release oral delivery system (OROS). This advanced drug delivery technology, applied successfully to a number of products in different therapeutic areas, uti-lises osmotic pressure as the driving force for delivery of pharmacotherapy and provides release of medication at a constant rate over extended periods.
There are four different structural variants of OROS technology. The one utilised in paliperidone ER is the advanced longitudinally compressed tablet (LCT) multilayer formulation, consisting of an osmotically active trilayer core, composed of two distinct drug layers and an osmotic push compartment. This formulation, designed to deliver paliperidone at a relatively constant rate over a 24-hour period, results in release of drug at a gradually ascending rate and with reduced fluctuations between drug peak and trough plasma concentrations at steady state (for example, 38% paliperidone ER vs 125% risperidone immediate-release).
The major advantage of this formulation should be in terms of improved patient compliance, as it can be started at a therapeutic dosage and administered once daily with no need for initial titration. With regard to safety, the use of this formulation should prevent or minimise the risk of adverse effects presumably related to peak concentrations, including those occurring in the first few days of treatment with rapidly increasing doses (ie, acute dystonia and postural hypotension). According to the prescribing information, the tablet should be swallowed whole and not chewed, split or crushed in order to protect the integrity of the OROS delivery system.
Like risperidone, paliperidone is a potent dopamine D2 antagonist with predominant serotonin 5HT2A antagonistic activity.[12,13] In addition, paliperidone has some affinity with H1-histaminergic receptors, alpha1- and alpha2- adrenergic receptors, which may explain weight gain, orthostatic hypotension or sedative side-effects. At the same time, it has no affinity for cholinergic muscarinic receptors and beta1- and beta2-adrenergic receptors.
Paliperidone is well absorbed from the gastrointestinal tract, but due to the OROS formulation of the ER tablet plasma concentrations take about 24 hours to reach peak and 4–5 days to achieve steady state.[4,5] Approximately 74% of the drug is bound to plasma protein. Paliperidone undergoes very limited hepatic metabolism and is mainly excreted unchanged in the urine (60%); its terminal half-life is about 24 hours. Paliperidone does not substantially inhibit or induce the activity of various CYP isoenzymes, so it is unlikely to interfere with the biotransformation of concomitantly administered medications. Similarly, due to its limited hepatic metabolism, concomitant administration of inhibitors or inducers of CYP isoforms is not expected to have a significant effect on the pharmacokinetics of paliperidone. The low potential of paliperidone for hepatic drug–drug interactions may represent an important advantage compared with risperidone and most second-generation antipsychotics.
Clinical evidence for paliperidone ER
The efficacy and safety of paliperidone ER in acute and maintenance treatment of patients with schizophrenia have been documented in four multicentre, randomised, double-blind and placebo-controlled studies. [14–17] The acute efficacy was investigated in three similar six-week trials in patients experiencing an acute exacerbation.[14–16] The results of these studies demonstrated significant improvements in symptoms of schizophrenia, as assessed by the Positive and Negative Syndrome Scale (PANSS), as well as in personal and social functioning. While all doses of paliperidone ER used in these trials (3, 6, 9, 12 and 15mg/day) were efficacious, the 3mg dose was least effective. Thus, paliperidone ER 6mg/day is the suggested starting dose for treatment of schizophrenia. A double-blind, placebo-controlled, long-term study documented that paliperidone ER (flexibly dosed at 3–15mg/day) was superior to placebo in preventing recurrence after stabilisation.  A recent study in patients with an incomplete response to a previous treatment with risperidone has demonstrated that paliperidone ER is more effective than placebo in reducing symptoms and producing functional gains.
Based on the available clinical trials, paliperidone ER appears to be a safe and well-tolerated agent with a very low incidence of acute and chronic sideeffects in comparison with placebo.[14–17] In general, the adverse effects most commonly observed in patients treated with paliperidone ER 3–12mg/day and occurring with an incidence >5% included headache, anxiety, dizziness, somnolence and tachycardia. As with risperidone, the most important side-effects of paliperidone ER concern extrapyramidal symptoms and increase in prolactin levels. Paliperidone ER has an extrapyramidal tolerability profile comparable to risperidone, with low risk for extrapyramidal symptoms at doses of 3–6mg/day and higher rates of movement disorders (ie, akathisia and parkinsonism), with increasing doses. Paliperidone ER elevates prolactin levels in a fashion similar to risperidone. However, sexual-endocrine tolerability is not associated with a significant increase in prolactin plasma concentrations, with limited reports of clinically relevant adverse effects related to hyperprolactinaemia, including galactorrhoea, gynaecomastia, amenorrhoea, anorgasmia and abnormal sexual function. Furthermore, no evidence of clinically relevant metabolic dysfunction in terms of glucose, insulin, lipid or triglyceride changes has been observed in patients treated with paliperidone ER, while a dose-related increase in body weight (although lower compared with clozapine and olanzapine) was observed in short- and long-term studies.14–17 Paliperidone may cause a modest increase in the corrected QT interval (QTc) and should be avoided in combination with other drugs that are known to prolong the QTc interval. Orthostatic hypotension was not commonly reported during paliperidone ER, presumably due to slow release of the medication from the ER formulation. Preliminary long-term data (up to 52 weeks) appear to confirm the findings from shortterm studies indicating a low liability to cause tardive dyskinesia and metabolic effects, such as weight gain, hyperglycaemia and lipid dysregulation.[5,9] Available efficacy and safety data from elderly patients are also promising.
Paliperidone ER is the only currently available new antipsychotic to use the OROS extended-release technology. This formulation was specifically designed to ensure a gradual rise in plasma concentration of paliperidone, which allows treatment to begin with a therapeutically effective starting dose from the first day without the need for initial dose titration to prevent orthostatic hypotension, and to provide more stable plasma concentrations. Therefore, this formulation is expected to improve patient compliance and tolerability profile and may contribute to lower discontinuation rates.
Another theoretical advantage of paliperidone ER is represented by its minimal hepatic biotransformation resulting in a lower potential for drug–drug and drug– disease interactions as compared with risperidone and other newer antipsychotics. Randomised clinical trials conducted so far have documented that paliperidone ER is an effective and well-tolerated agent and provides a new treatment option in patients with schizophrenia. The recommended starting and target dose is 6mg/ day. While higher doses may produce further benefit, this strategy is mitigated by a dose-related increase in some adverse effects such as extrapyramidal symptoms, weight gain and QTc prolongation.
Further studies, in particular long-term tolerability and head-to-head comparative trials with other antipsychotics, are eagerly awaited to better define the place of paliperidone ER in the treatment of patients with schizophrenia.
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