In the 9 months since paliperidone extended-release was FDA-approved for schizophrenia, the 3 acute pivotal trials supporting its approval have been published.1-3 They join a handful of post hoc analyses of this second-generation antipsychotic (SGA) in schizophrenia subgroups, including patients over age 65, recently diagnosed patients, and those with predominant negative symptoms.
This article discusses the evidence and paliperidone ER’s probable clinical benefits and adverse effects, with focus on its:
- pharmacodynamics and pharmacokinetics
- potential efficacy in schizophrenia and for specific patients and symptoms
- safety and tolerability.
How does paliperidone ER work?
Paliperidone ER was approved for schizophrenia treatment in December 2006 based on three 6-week, randomized, placebo-controlled trials. Paliperidone ER is the active metabolite of risperidone (9-OH risperidone) delivered in a once-daily, time-released formulation (Table 1).
Pharmacodynamics. Similar to risperidone, paliperidone ER has high binding affinity for dopamine (D2) and serotonin (5-HT2A) receptors, with additional affinity for histaminic (H1) and adrenergic receptors (alpha1 and alpha2) but not for muscarinic-cholinergic receptors.
Pharmacokinetics. After oral administration, the medication is widely and rapidly distributed. The drug’s terminal half-life is about 23 hours, and steady-state concentration is reached in 4 to 5 days.4,5
Thus paliperidone ER—when compared with risperidone and other antipsychotics that are metabolized primarily in the liver—is less likely to be involved in hepatic drug-drug or drug-disease interactions. However, some drugs that can induce CYP-450 enzymes—such as carbamazepine—may affect paliperidone’s metabolism.7
Paliperidone has an osmotic controlled-release oral delivery system (OROS®) for steady medication delivery across 24 hours8 (Table 2).1-3 The tablet consists of an osmotically active tri-layer core surrounded by a semipermeable membrane. When the tablet is swallowed, the membrane controls the rate of water reaching the tablet core, which determines the rate of drug delivery.6 The result is less variation between peak and trough drug concentrations, compared with immediate-release formulations.
Table 1
How paliperidone ER compares with risperidone
| Characteristic | Paliperidone ER | Risperidone |
|---|---|---|
| Formulation | OROS extended-release | Immediate release |
| Active moiety | 9-OH risperidone | Risperidone plus 9-OH risperidone |
| Metabolism | Primarily renal | Primarily hepatic |
| Drug interactions | Minimal | Primarily through cytochrome P-450 enzyme 2D6 |
| Dosing | Start at target dose | Titrate to target dose |
| OROS: osmotic controlled-release oral delivery system | ||
Paliperidone ER’s clinical characteristics
| Second-generation antipsychotic approved for schizophrenia |
| 9-OH active metabolite of risperidone |
| Osmotic controlled-release system provides steady-state drug delivery over 24 hours |
| Terminal half-life (time for 50% of drug to be eliminated from the body) ~23 hours |
| Available in 3-mg, 6-mg, and 9-mg tablets; recommended starting dose is 6 mg/d, and labeled dose range is 3 to 12 mg/d |
| Excreted primarily by the kidney; maximum recommended dose for patients with oderate to severe renal impairment is 3 mg/d |
| Source: References 1-3 |
Clinical use
Paliperidone ER offers potential therapeutic benefits in treating schizophrenia patients, although not without the risk of adverse events such as extrapyramidal symptoms (EPS) (Table 3).1-3
Patient selection. Because of its slow-release formulation and relatively stable plasma concentrations, paliperidone ER might be useful for patients who are highly sensitive to antipsychotics’ side effects. In particular, paliperidone ER might be ideal for patients who respond to but may not tolerate risperidone.
Paliperidone ER appears to be safe in patients with liver disease. Its primary renal excretion should minimize the risk of hepatic-related drug interactions in patients taking multiple medications.
Dosage and titration. For treating schizophrenia, the suggested starting dose of paliperidone ER is 6 mg/d taken in the morning. In the 3 pivotal trials, 6 mg was the lowest dose to show broad efficacy with minimal adverse events.9
For many patients, the 6-mg starting dose will be the therapeutic dose. When needed, the dose may be increased in 3-mg increments every 1 to 2 weeks to a maximum 12 mg/d (a 15-mg dose was used in clinical trials, but the adverse effects out-weighed the benefits). Lower maximum doses are recommended for patients with renal impairment:
- 6 mg/d for those with creatinine clearance ≥50 to
- 3 mg/d for those with creatinine clearance 10 to 10
Safety and tolerability. Pooled data from the 3 trials indicate that adverse events (AEs) occurred during treatment in 66% to 77% of patients receiving paliperidone ER vs 66% in placebo groups. The most common AEs were headache (11% to 18%), insomnia (4% to 12%), and anxiety (6% to 9%).9