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Cited by 35Schizophrenia research and treatmentPharmaceutical studies and practicesPharmacogenetics and Drug Metabolism

Population Pharmacokinetics and Prediction of Dopamine D2 Receptor Occupancy After Multiple Doses of RBP‐7000, a New Sustained‐Release Formulation of Risperidone, in Schizophrenia Patients on Stable Oral Risperidone Treatment

Laffont, Celine M., Gomeni, Roberto, Zheng, Bo, Heidbreder, Christian, Fudala, Paul J., Nasser, Azmi F.·2014·Clinical Pharmacokinetics
DOI 10.1007/s40262-014-0132-7
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Abstract

Background and objectives RBP-7000 is a long-acting formulation of risperidone administered once monthly via subcutaneous (SC) injections for the treatment of schizophrenia. The objectives of the present study were to characterize the pharmacokinetics of RBP-7000 after multiple doses in schizophrenic patients on stable oral risperidone therapy and to evaluate the switch between oral risperidone and SC injections of RBP-7000.Methods Data were collected in a phase IIa, open-label, multiple-ascending-dose study where 45 patients clinically stabilized on oral risperidone (2, 3 or 4 mg/day) were switched to receive 60, 90 or 120 mg/month SC injections of RBP-7000, respectively. Patients were thereafter switched back to oral risperidone. An integrated population pharmacokinetic model describing simultaneously risperidone and 9-hydroxyrisperidone after risperidone oral intake and RBP-7000 administration was developed in NON-MEM using 5,232 quantifiable plasma concentrations. Predictions of dopamine D2 receptor occupancy were derived using a previously published model.Results A two-compartment model with first-order absorption was selected for oral risperidone, while a three-compartment model with first-order absorption and a transit compartment absorption model was selected for RBP-7000. Body mass index was identified as a significant covariate affecting the initial absorption of risperidone following RBP-7000 injection. Steady state was reached after the second or third RBP-7000 injection but plasma concentrations close to steady-state values were obtained right after the first injection when switching from oral risperidone therapy. Predicted dopamine D2 receptor occupancy after repeated doses of 90 and 120 mg showed less fluctuation than after oral risperidone with acceptable ranges for clinical efficacy and a potentially safer profile with respect to extrapyramidal side effects.Conclusion This analysis provided additional insight into the pharmacokinetics of RBP-7000 and for the comparison with oral risperidone treatment. The established model was used to support the design of a planned phase III study.

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Authors
Laffont, C. M., Gomeni, R., Zheng, B., Heidbreder, C., Fudala, P. J., & Nasser, A. F.
Affiliations
Reckitt Benckiser (United States) (US)
Corresponding author
Nasser, Azmi F.
ORCID
Venue
Clinical Pharmacokinetics
Publisher
Springer Science and Business Media LLC
Published
2014-01-24
Volume
53
Issue
6
Pages
533-543
ISSN
  • 0312-5963 (ISSN-L)
  • 1179-1926
DOI
10.1007/s40262-014-0132-7
OpenAlex
W1994627117
Cited by
35
References
22
Citations by year
2026: 1 · 2025: 5 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 2
FWCI
2.80
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Clinical Pharmacokinetics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
risperidone, long-acting injectable antipsychotics, sustained-release formulation, subcutaneous injection, schizophrenia, population pharmacokinetics, dopamine D2 receptor occupancy, paliperidone, extrapyramidal symptoms
MeSH terms
Paliperidone Palmitate, Administration, Oral, Adult, Delayed-Action Preparations, Dose-Response Relationship, Drug, Female, Humans, Injections, Subcutaneous, Isoxazoles, Male, Middle Aged, Models, Biological, Pyrimidines, Schizophrenia, Antipsychotic Agents, Receptors, Dopamine D2, Risperidone, Young Adult

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