Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia

Abstract

Paliperidone palmitate is an investigational, injectable atypical antipsychotic. The safety and tolerability of initiating treatment with paliperidone palmitate via deltoid versus gluteal injections given once monthly, and of switching injection sites, in adults with stable schizophrenia were assessed. In this crossover trial, stable outpatients (N = 252) were randomly assigned 1:1:1 to 3 dose groups (paliperidone palmitate 50, 75, or 100 mg eq.) and 2 treatment sequences (blinded to dose): deltoid muscle (period 1 [13 weeks]) followed by gluteal muscle (period 2 [12 weeks]) or the reverse. The intent-to-treat analysis set had 249 patients: mean age = 43 (SD: 12.8) years; 57% men, 81% white, baseline mean Positive and Negative Syndrome Scale (PANSS) total score = 56 (SD: 11.5). A total of 170 (68%) patients completed the study, with a similar proportion completing each treatment sequence. The incidence of systemic treatment-emergent adverse events (TEAEs) was similar between the 2 injection sites across doses during period 1 (deltoid [D]: 61% to 67%; gluteus [G]: 58% to 65%), and during the last 8 weeks of the 2 study periods (DG: 32% to 45% [period 1], 29% to 42% [period 2]; GD: 31% to 40% [period 1], 30% to 41% [period 2]). During the first treatment week, median plasma paliperidone concentrations were higher with treatment initiation in the deltoid muscle compared with the gluteal muscle. At apparent steady state, there was little difference in plasma paliperidone concentrations between the deltoid and gluteus sites for a given dose. Local tolerability was slightly better with gluteal injections. Patient preference for injection sites differed between geographical regions, e.g. patients from the US preferred deltoid to gluteal sites. The most common (≥ 5% overall) TEAEs were: (period 1) insomnia, anxiety, headache, and agitation; and (period 2) insomnia, psychotic disorder, weight increased, and tachycardia. Paliperidone palmitate treatment was tolerated, irrespective of injection site, and thus could offer the choice of administration into either the deltoid or gluteal muscle to meet patient and physician preference.

Introduction

Schizophrenia, often a chronic disease, requires uninterrupted, long-term therapy with antipsychotic medications (Keith et al., 2004). However, partial or total nonadherence with oral antipsychotics remains widespread among patients with schizophrenia, and is associated with significant increases in the risk of relapse and rehospitalization (Kane et al., 1998, Nasrallah, 2007). Compared with oral formulations, the long-acting injectable (LAI) atypical antipsychotics offer decreased dosing frequency, improved bioavailability, and more stable plasma concentrations of drug. In addition, the regular monitoring that results with injectable treatment can enhance treatment adherence in patients with schizophrenia, facilitating relapse prevention and improving the long-term prognosis (Barnes and Curson, 1994, Kane et al., 1998, Kane, 2003).

Paliperidone, the active metabolite of the atypical antipsychotic risperidone, is an approved antipsychotic medication for the treatment of schizophrenia that exhibits the characteristic dopamine type 2 and serotonin type 2A antagonism of the second-generation antipsychotic drugs. The efficacy and tolerability of the oral extended-release formulation of paliperidone (paliperidone ER) have been established in randomized controlled studies (Kane et al., 2007, Kramer et al., 2007, Marder et al., 2007).

Paliperidone palmitate is an investigational LAI aqueous suspension formulation of paliperidone, designed for once-monthly intramuscular (i.m.) injections in the treatment of schizophrenia. Paliperidone palmitate has extremely low water solubility, and thus diffuses slowly into the systemic circulation after an i.m. injection and provides sustained plasma concentrations of paliperidone, the pharmacologically active fraction. Treatment with paliperidone palmitate does not require oral supplementation during initiation as its formulation allows immediate gradual release of the drug.

The efficacy and safety of paliperidone palmitate in the treatment of schizophrenia have been evaluated in several randomized, double-blind, controlled studies (Hough et al., 2008, Kramer et al., Submitted for publication, Nasrallah et al., Submitted for publication), all of which administered treatment in the gluteus muscle site. A previous study with another atypical LAI antipsychotic (Risperdal® Consta®, Janssen, Titusville, NJ) demonstrated bioequivalent plasma exposure following deltoid and gluteal injections (Thyssen et al., 2008). In contrast, in a phase 1 study of paliperidone palmitate, deltoid injections resulted in earlier and higher peak plasma paliperidone concentrations as compared with gluteal injections (Cleton et al., 2008). It was important, therefore, to specifically assess the safety and tolerability of paliperidone palmitate administered as deltoid versus gluteal injection in patients with schizophrenia. The flexibility to administer paliperidone palmitate injections in either the deltoid or gluteus muscles increases the availability of injection sites from 2 to 4, and thus increases treatment options for patients, based on their preferences and that of their physician.

The objective of the current study was to evaluate the safety and tolerability of: (i) initiating paliperidone palmitate treatment in the deltoid injection site, and (ii) switching the injection site from deltoid to gluteus (DG) or from gluteus to deltoid (GD) during treatment with paliperidone palmitate 50, 75, or 100 mg eq. in patients with stable schizophrenia.