Risperidone (RIS), an atypical antipsychotic drug, is used for the treatment of psychoses associated with schizophrenia and other psychiatric disorders in adult and pediatric populations. An oral dispersible tablet formulation of risperidone has been developed. This study was conducted to provide support for marketing authorization of this drug in China.
This study was designed to compare the pharmacokinetic (PK) properties and bioavailability of 2 RIS formulations—the dispersible formulation (test) and a branded formulation (reference) in healthy male Chinese volunteers.
This single-dose, randomized-sequence, open-label, 2-period crossover study involved 22 healthy male Chinese volunteers. Equal numbers of eligible participants were randomly assigned to receive either the test drug (2 mg) or the same dose of the reference formulation, followed by a 2-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Blood samples were collected before dosing and at 0.33, 0.67, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72, and 96 hours after dosing. Plasma concentrations of RIS and its active metabolite, 9-hydroxyrisperidone (9-OH-RIS), were measured using LC-MS/MS. The safety profile was evaluated by recording adverse events (AEs), assessed using physical examination including vital signs, spontaneous reporting, and clinical laboratory results. The 2 formulations were considered to have met the requirements for bioequivalence if the 90% CIs for the log-transformed Cmax and AUC values were within the predetermined ranges of 75% to 133% and 80% to 125%, respectively, according to the guidelines of the State Food and Drug Administration (SFDA) of China.
All 22 volunteers (mean [SD] age, 22.2 [1.98] years; weight, 64.07 [5.93] kg; height, 173  cm; and body mass index, 21.2 [1.67] kg/m2) that were enrolled completed the study. For RIS, the 90% CIs for the ratios of Cmax, AUC0–t, and AUC0−∞ were 93.2% to 116.7%, 97.9% to 111.3%, and 98.0% to 111.6%, respectively. For 9-OH-RIS, the 90% CIs were 95.8% to 113.9%, 100.2% to 109.7%, and 100.5% to 110.3%, respectively. All values were within the predetermined bioequivalence range. Seven AEs were reported somnolence (4 subjects [9.1%]) and dizziness (3 subjects [6.8%]). All AEs were transient and considered mild by physicians.
The test (dispersible) and reference tablets met the regulatory criteria for bioequivalence as defined by the SFDA. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TRC-12001996.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Clinical Therapeutics
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Effect of CYP2D6, CYP3A5, and MDR1 genetic polymorphisms on the pharmacokinetics of risperidone and its active moiety.J Clin Pharmacol. 2010; 50: 659-666
- Serum levels of risperidone and its metabolite 9-hydroxyrisperidone: correlation between drug concentration and clinical response.Ther Drug Monit. 2009; 31: 475-481
- Pharmacology and clinical experience with risperidone.Expert Opin Pharmacother. 2000; 7: 1441-1453
- Effects of CYP2D6 genotypes on plasma concentrations of risperidone and enantiomers of 9-hydroxyrisperidone in Japanese patients with schizophrenia.J Clin Pharmacol. 2003; 43: 122-127
- Risperidone: an open-label, observational study of the efficacy, tolerability, and prescribing behavior in acutely exacerbated patients with schizophrenia.J Clin Psychopharmacol. 2005; 25: 293-300
- Serum prolactin levels, plasma risperidone levels, polymorphism of cytochrome P450 2D6 and clinical response in patients with schizophrenia.J Psychopharmacol. 2007; 21: 837-842
- Paliperidone extended-release for the treatment of schizophrenia.Pharmacotherapy. 2008; 28: 1283-1298
- Paliperidone extended release: a review of its use in the management of schizophrenia.Drugs. 2010; 70: 1295-1317
- Recent technological advances in oral drug delivery a review.Pharm Sci Technol Today. 2000; 3: 138-145
- Influence of drug properties and routes of drug administration on the design of sustained and controlled release systems.in: Lee V.H. Controlled Drug Delivery-Fundamentals and Actions. Marcel Dekker, New York, NY1987: 3-94
- Pharmacokinetic comparison of fast-disintegrating and conventional tablet formulations of risperidone in healthy volunteers.Clin Ther. 2003; 25: 1687-1699
- Pharmacokinetics and bioequivalence evaluation of risperidone in healthy male subjects with different CYP2D6 genotypes.Arch Pharm Res. 2006; 29: 525-533
- Relative bioavailability of two oral formulations of risperidone 2 mg: a single-dose, randomized-sequence, open-label, two-period crossover comparison in healthy Brazilian volunteers.Clin Ther. 2010; 32: 2106-2115
- WMA Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects.Accessed March 26, 2006)
- Note for Guidance on Good Clinical Practice.Accessed March 26, 2006)
- Guideline for Good Clinical Practice [in Chinese].Accessed March 5, 2009)
- Guideline for bioavailability and bioequivalence studies of generic drug products [in Chinese].Accessed March 5, 2009)
- Advance in search for pharmacokinetics of an atypical antipsychotic: risperidone [in Chinese].Chin J Clin Pharmacol. 2004; 20: 228-233
- Determination of risperidone and enantiomers of 9-hydroxyrisperidone in plasma by LC-MS/MS.J Chromatogr B. 2007; 852: 497-504
- Guidance for Industry: Bioanalytical Method Validation.Accessed March 3, 2009)
- Functions of the DAS software for pharmacological calculation.Chin J Clin Pharmacol Ther. 2002; 7: 562-564
- Approval of Supplemental New Drug Application 21-066/S-011.Accessed September 6, 2007)
- Guidance for Industry: Bioavailability and bioequivalence studies for orally administered drug products-general considerations.Accessed January 30, 2009)
- Paliperidone for schizophrenia.Am J Health Syst Pharm. 2008; 65: 403-413
- Paliperidone extended-release tablets for the acute and maintenance treatment of schizophrenia.Clin Ther. 2008; 32: 231-248
- Relative bioavailability and pharmacokinetic comparison of two 2-mg risperidone tablet formulations: a single dose, randomized-sequence, double-blind, 2-way crossover study in healthy male volunteers in Thailand.Clin Ther. 2010; 32: 1842-1853
- Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4.Naunyn-Schmiedebergs Arch Pharmacol. 1999; 359: 147-151
Published online: May 17, 2012
Accepted: April 25, 2012
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.