Population Pharmacokinetic Analysis to Support and Facilitate Switching from Risperidone Formulations to Rykindo in Patients with Schizophrenia

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Abstract

Introduction

RYKINDO® (Rykindo) is a novel, long-acting injectable risperidone formulation administered biweekly (Q2W) through intramuscular gluteal injection for the treatment of schizophrenia in adult patients. This analysis was conducted to demonstrate that the clinical outcomes of Rykindo are equivalent to those of RISPERDAL CONSTA® (Consta; Q2W), and to establish a dosing methodology to switch from Consta to Rykindo, as well as to introduce Rykindo to patients who are currently on oral RISPERDAL® (Risperdal).

Methods

Population pharmacokinetic (PK) models for Rykindo and Consta were developed using a nonlinear mixed-effects model with the data from phase 1 studies. A model-based simulation was also conducted using NONMEM.

Results

The PK profiles of Rykindo and Consta were adequately represented by a one-compartment model with an immediate release followed by an intermediate and third main release. Drug release of Rykindo was faster than for Consta, reaching steady state approximately 2–3 weeks earlier. The exposures of the active moiety of Rykindo and Consta were comparable at steady state. Model-based simulation indicated that switching from Consta to Rykindo requires administration of the first Rykindo injection within 4–5 weeks following the last Consta injection. For patients taking Risperdal, introducing Rykindo with 1 week of Risperdal supplemental for once-daily dosing (QD) can achieve comparable or superior exposure to that of Consta with 3 weeks of oral QD supplements. A dosing window of ± 3 days for Rykindo was recommended.

Conclusions

This established approach provides guidance to physicians to initiate Rykindo therapy in adult patients with schizophrenia.

Trial Registration

ClinicalTrials.gov identifier, NCT02055287, NCT02186769 and NCT02091388.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40120-024-00578-w.

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Most cited references 18

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Schizophrenia

Allan Ropper, Stephen R. Marder, Tyrone Cannon (2019)

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Impact of long-acting injectable antipsychotics on medication adherence and clinical, functional, and economic outcomes of schizophrenia

Gabriel Kaplan, Julio Casoy, Jacqueline Zummo (2013)

Schizophrenia is a debilitating chronic disease that requires lifelong medical care and supervision. Even with treatment, the majority of patients relapse within 5 years, and suicide may occur in up to 10% of patients. Poor adherence to oral antipsychotics is the most common cause of relapse. The discontinuation rate for oral antipsychotics in schizophrenia ranges from 26% to 44%, and as many as two-thirds of patients are at least partially nonadherent, resulting in increased risk of hospitalization. A very helpful approach to improve adherence in schizophrenia is the use of long-acting injectable (LAI) antipsychotics, although only a minority of patients receive these. Reasons for underutilization may include negative attitudes, perceptions, and beliefs of both patients and health care professionals. Research shows, however, significant improvements in adherence with LAIs compared with oral drugs, and this is accompanied by lower rates of discontinuation, relapse, and hospitalization. In addition, LAIs are associated with better functioning, quality of life, and patient satisfaction. A need exists to encourage broader LAI use, especially among patients with a history of nonadherence with oral antipsychotics. This paper reviews the impact of nonadherence with antipsychotic drug therapy overall, as well as specific outcomes of the schizophrenia patient, and highlights the potential benefits of LAIs.

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Relapse contribute to treatment resistance?Antipsychotic response in first- vs. second-episode schizophrenia

Hiroyoshi Takeuchi, Cynthia Siu, Gary Remington … (2018)

Although some studies have suggested that relapse may be associated with antipsychotic treatment resistance in schizophrenia, the number and quality of studies is limited. The current analysis included patients with a diagnosis of first-episode schizophrenia or schizoaffective disorder who met the following criteria: (1) referral to the First-Episode Psychosis Program between 2003 and 2013; (2) treatment with an oral second-generation antipsychotic according to a standardized treatment algorithm; (3) positive symptom remission; (4) subsequent relapse (i.e., second episode) in association with non-adherence; and (5) reintroduction of antipsychotic treatment with the same agent used to achieve response in the first episode. The following outcomes were used as an index of antipsychotic treatment response: changes in the brief psychiatric rating scale (BPRS) total and positive symptom scores and number of patients who achieved positive symptom remission and 20 and 50% response. A total of 130 patients were included in the analyses. Although all patients took the same antipsychotic in both episodes, there were significant episode-by-time interactions for all outcomes of antipsychotic treatment response over 1 year in favor of the first episode compared to the second episode (50% response rate: 48.7 vs. 10.4% at week 7; 88.2 vs. 27.8% at week 27, respectively). Although antipsychotic doses in the second episode were significantly higher than those in the first episode, results remained unchanged after adjusting for antipsychotic dose. The present findings suggest that antipsychotic treatment response is reduced or delayed in the face of relapse following effective treatment of the first episode of schizophrenia.

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Author and article information

Contributors

Wenyan Wang:

ORCID: http://orcid.org/0000-0003-0589-654X

wangwenyan@ytu.edu.cn

Kaoxiang Sun: sunkx@ytu.edu.cn

Journal

Journal ID (nlm-ta): Neurol Ther

Journal ID (iso-abbrev): Neurol Ther

Title: Neurology and Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 2193-8253

ISSN (Electronic): 2193-6536

Publication date (Electronic): 20 January 2024

Publication date PMC-release: 20 January 2024

Publication date Collection: April 2024

Volume: 13

Issue: 2

Pages: 355-372

Affiliations

[1 ]School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, ( https://ror.org/01rp41m56) Yantai, Shandong China

[2 ]Research and Development Center, Luye Pharma, ( https://ror.org/04apy5543) Yantai, Shandong China

[3 ]National Key Laboratory of Advanced Drug Delivery and Release Systems, Yantai, Shandong China

[4 ]ClinPharm Solutions LLC, Chester, NJ USA

[5 ]Global Clinical Development, Luye Pharma (US), Ltd., Princeton, NJ USA

[6 ]GRID grid.477096.b, ISNI 0000 0004 0626 519X, CenExel–CNS, ; Garden Grove, CA USA

Author information

Wenyan Wang http://orcid.org/0000-0003-0589-654X

Article

Publisher ID: 578

DOI: 10.1007/s40120-024-00578-w

PMC ID: 10951188

PubMed ID: 38244179

SO-VID: 375d433d-0db6-40e3-b50c-4c1602ca5f23

License:

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 15 November 2023

Date accepted : 2 January 2024

Funding

Funded by: This study was sponsored by Luye Pharma

Custom metadata

Keywords: risperidone,long-acting injection,population pharmacokinetic model,switching from consta to rykindo,dosing window

Data availability:

Keywords: risperidone, long-acting injection, population pharmacokinetic model, switching from consta to rykindo, dosing window

Population Pharmacokinetic Analysis to Support and Facilitate Switching from Risperidone Formulations to Rykindo in Patients with Schizophrenia

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Abstract

Introduction

Methods

Results

Conclusions

Trial Registration

Supplementary Information

Related collections

Core Readings in Statistical Mediation Analysis

Most cited references 18

Schizophrenia

Impact of long-acting injectable antipsychotics on medication adherence and clinical, functional, and economic outcomes of schizophrenia

Relapse contribute to treatment resistance?Antipsychotic response in first- vs. second-episode schizophrenia

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Contributors

Journal

Affiliations

Author information

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History

Funding

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