Progress in Neuro-Psychopharmacology and Biological Psychiatry
Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia☆,☆☆
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.
Section snippets
Methods
The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. All patients provided written informed consent before entering the study.
Patient characteristics and disposition
Of the total 290 patients screened, 252 patients were randomly assigned with approximately equal allocation (40–46 per group) to the 6 treatment groups (a combination of the 3 dose groups and 2 treatment sequences) (Fig. 1). A total of 249 (99%) randomized patients were included in the ITT and safety analysis sets and 185 (73%) were included in the MITT analysis set; 170 out of the 249 randomized (68%) patients completed the study, with similar proportions completing each of the treatment
Discussion
This is the first study to examine the tolerability of paliperidone palmitate, an investigational LAI atypical antipsychotic for the treatment of schizophrenia, administered in a different site from the gluteus muscle site. Paliperidone palmitate was tolerated following initiation of treatment via injection in the deltoid, compared with the gluteus. In addition, there were no safety or tolerability concerns associated with changing injection sites after 3 months of treatment.
The occurrence of
Conclusion
Treatment with the investigational LAI atypical antipsychotic paliperidone palmitate was tolerated in patients with schizophrenia, irrespective of the injection site (gluteus or deltoid) used. During the first week of treatment, the 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
Conflict of interest statement
This study was funded by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Dr. J.P. Lindenmayer was a principal investigator for the study, has received research grants from Johnson & Johnson and has a consultant relationship with Johnson & Johnson, and has received grant support from Astra Zeneca, Lilly and Pfizer. Drs. Gopal, Hough, Lim, Yuen, and Ms. Melkote are employed by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Drs. Eerdekens and Herben are employed by
Role of funding source
Johnson & Johnson Pharmaceutical Research & Development, L.L.C. funded this study and was responsible for study design and data collection, analysis and its interpretation. The sponsor also was responsible for deciding to publish the data. Many of the authors are employees of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., as noted.
Acknowledgements
Dr. Madhavi Patil (SIRO Clinpharm Pvt. Ltd.) provided writing assistance and Dr. Wendy P. Battisti (Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) provided additional editorial support for this manuscript.
We thank the following investigators for their participation in this study: Belgium: Morel, Jean-François, MD; Dujardin, Stephane, MD; Strul, John, MD Bulgaria: Akabaliev, Valentin H, Assoc Prof, MD; Jivkov, Lubomir L, MD; Popov, Georgi I, Assoc Prof, MD, PhD Czech Republic:
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Previous presentations: These data were presented at the Society of Biological Psychiatry Annual Scientific Meeting, May 2008, American Psychiatric Association Annual Meeting, May 2008, and the Institute of Psychiatric Services Annual Meeting, October 2008.
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This study is registered http://www.clinicaltrials.gov:NCT00119756.