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Clinical Pharmacokinetics

, Volume 53, Issue 6, pp 533–543 | Cite as

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

  • Celine M. Laffont
  • Roberto Gomeni
  • Bo Zheng
  • Christian Heidbreder
  • Paul J. Fudala
  • Azmi F. Nasser
Original Research Article

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 NONMEM 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.

Keywords

Risperidone Paliperidone Population Pharmacokinetic Model Visual Predictive Check Paliperidone Palmitate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Conflict of interest

B. Zheng, C. Heidbreder, P. J. Fudala and A. F. Nasser were full-time employees of Reckitt Benckiser Pharmaceuticals, Inc. C. M. Laffont and R. Gomeni were consultants for Reckitt Benckiser Pharmaceuticals, Inc. This project was funded by Reckitt Benckiser Pharmaceuticals, Inc., and there was no external funding.

Supplementary material

40262_2014_132_MOESM1_ESM.pdf (1.3 mb)
Supplementary material 1 (PDF 1295 kb)

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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Celine M. Laffont
    • 1
  • Roberto Gomeni
    • 2
  • Bo Zheng
    • 3
  • Christian Heidbreder
    • 3
  • Paul J. Fudala
    • 3
  • Azmi F. Nasser
    • 3
  1. 1.PharmacometricaLa FouilladeFrance
  2. 2.AlleantisResearch Triangle ParkUSA
  3. 3.Reckitt Benckiser Pharmaceuticals, Inc.RichmondUSA

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