CNS Drugs

, Volume 31, Issue 4, pp 273–288 | Cite as

Dosing and Switching Strategies for Paliperidone Palmitate 3-Month Formulation in Patients with Schizophrenia Based on Population Pharmacokinetic Modeling and Simulation, and Clinical Trial Data

  • Mats O. MagnussonEmail author
  • Mahesh N. Samtani
  • Elodie L. Plan
  • E. Niclas Jonsson
  • Stefaan Rossenu
  • An Vermeulen
  • Alberto Russu
Review Article


Paliperidone palmitate 3-month formulation (PP3M), a long-acting injectable atypical antipsychotic, was recently approved in the US and Europe for the treatment of schizophrenia in adult patients who have already been treated with paliperidone palmitate 1-month formulation (PP1M) for ≥4 months. This article reviews the pharmacokinetic rationale for the approved dosing regimens for PP3M, dosing windows, management of missed doses and treatment discontinuation, switching to other formulations, and dosing in special populations. Approved PP3M dosing regimens are based on the comparisons of simulations with predefined dosing regimens using paliperidone palmitate and oral paliperidone extended release (ER) population pharmacokinetic models (one-compartment model with two saturable absorption processes for PP3M; one-compartment model with parallel zero- and first-order absorption for PP1M; two-compartment model with sequential zero- and first-order absorption for ER) versus clinical trial data. Covariates were obtained by resampling subject covariates from the pharmacokinetics database for PP1M and PP3M. Simulation scenarios with varying doses and covariate values were generated. The population median and 90% prediction interval of the simulated concentration-time profiles were plotted for simulation outcomes evaluation. Simulations described in this paper provide (a) simulated plasma exposures for switching from PP1M to PP3M, (b) support for a once-every-3-months injection cycle, (c) information on dosing windows and managing missed doses of PP3M, (d) important guidance on PP3M dosing in special patient populations, and (e) key PP3M pharmacokinetic exposure metrics based on the population pharmacokinetic PP3M model. Population pharmacokinetics provided practical guidance to establish dosing regimens for PP3M.


Extended Release Paliperidone Population Pharmacokinetic Model Paliperidone Palmitate Mild Renal Impairment 
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.



The authors would like to thank Sebastian Ueckert for his contribution to the simulations and Tinka Tuinstra Ph.D., an employee of AUTHOR!, for her medical writing assistance, both sub-contractors of Pharmetheus.

Compliance with Ethical Standards

Conflict of Interest

M. O. Magnusson, E. L. Plan, and E. N. Jonsson are employees of Pharmetheus and received consultancy fees from Janssen Research & Development. M. N. Samtani, S. Rossenu, A. Vermeulen, and A. Russu are employees of Janssen Research & Development and own Johnson & Johnson stocks and/or stock options.


S. Ueckert and T. Tuinstra received consultancy fees from Janssen Research & Development for their work on this manuscript.

Supplementary material

40263_2017_416_MOESM1_ESM.docx (926 kb)
Supplementary material 1 (DOCX 924 kb)


  1. 1.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed., text revision [DSM-IV-TR]. Arlington (VA): American Psychiatric Association; 2000.Google Scholar
  2. 2.
    Andreasen NC. Symptoms, signs, and diagnosis of schizophrenia. Lancet. 1995;346(8973):477–81.CrossRefPubMedGoogle Scholar
  3. 3.
    Ascher-Svanum H, Faries DE, Zhu B, Ernst FR, Swartz MS, Swanson JW. Medication adherence and long-term functional outcomes in the treatment of schizophrenia in usual care. J Clin Psychiatry. 2006;67(3):453–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Di Pace C, Paletta S, Reggiori A, Maffini M, Chirico M, Mauri MC, Altamura AC. Paliperidone “long-acting” and plasma levels along 1 year of maintenance therapy in schizophrenia and schizoaffective disorder. Eur Neuropsychopharmacol. 2015;S2:525.CrossRefGoogle Scholar
  5. 5.
    US label of INVEGA® SUSTENNA® (Revised 01/2016). Available at: Accessed 10 May 2016.
  6. 6.
    EU label of TREVICTA® (last updated on eMC 09/2016). Available at Accessed 16 Dec 2016.
  7. 7.
    Keith SJ, Kane JM. Partial compliance and patient consequences in schizophrenia: our patients can do better. J Clin Psychiatry. 2003;64(11):1308–15.CrossRefPubMedGoogle Scholar
  8. 8.
    Remenar JF. Making the leap from daily oral dosing to long-acting injectables: lessons from the antipsychotics. Mol Pharm. 2014;11(6):1739–49.CrossRefPubMedGoogle Scholar
  9. 9.
    Gopal S, Gassmann-Mayer C, Palumbo J, Samtani MN, Shiwach R, Alphs L. Practical guidance for dosing and switching paliperidone palmitate treatment in patients with schizophrenia. Curr Med Res Opin. 2010;26(2):377–87.CrossRefPubMedGoogle Scholar
  10. 10.
    Ravenstijn P, Remmerie B, Savitz A, De Meulder M, Hough D, Gopal S, et al. Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: a phase-1, single-dose, randomized, open-label study. J Clin Pharmacol. 2016;56(3):330–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Berwaerts J, Liu Y, Gopal S, Nuamah I, Xu H, Savitz A, Coppola D, Schotte A, Remmerie B, Maruta N, Hough DW. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2015;72(8):830–9.CrossRefGoogle Scholar
  12. 12.
    Magnusson MO, Samtani MN, Plan EL, Jonsson EN, Rossenu S, Vermeulen A, et al. Population pharmacokinetic modeling of paliperidone palmitate 3-month formulation poster presented at PAGE 24; 2015. Abstr 3408.
  13. 13.
    Magnusson MO, Samtani MN, Plan EL, Jonsson EN, Rossenu S, Vermeulen A, et al. Population pharmacokinetics of a novel once-every 3 months, intramuscular formulation of paliperidone palmitate in patients with schizophrenia. Clin Pharmacokinet. 2016. [Epub ahead of print].Google Scholar
  14. 14.
    Samtani MN, Vermeulen A, Stuyckens K. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic. Clin Pharmacokinet. 2009;48(9):585–600.CrossRefPubMedGoogle Scholar
  15. 15.
    Pandina G, Lane R, Gopal S, Gassmann-Mayer C, Hough D, Remmerie B, et al. A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(1):218–26.CrossRefPubMedGoogle Scholar
  16. 16.
    Gopal S, Hough DW, Xu H, Lull JM, Gassmann-Mayer C, Remmerie BM, Eerdekens MH, Brown DW. Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study. Int Clin Psychopharmacol. 2010;25(5):247–56.CrossRefPubMedGoogle Scholar
  17. 17.
    Cirincione B, Redman M, Fiedler-Kelley J, et al. Population pharmacokinetics of paliperidone ER in healthy subjects and patients with schizophrenia [poster no. PI-21]. Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, 21–24 Mar 2007, Anaheim (CA).Google Scholar
  18. 18.
    Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ. NONMEM Users Guides. 1989 Icon development solutions, Ellicott City, Maryland.Google Scholar
  19. 19.
    R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN: 3-900051-07-0. Available at Accessed 18 Jan 2016.
  20. 20.
    Samtani MN, Gopal S, Gassmann-Mayer C, Alphs L, Palumbo JM. Dosing and switching strategies for paliperidone palmitate: based on population pharmacokinetic modelling and clinical trial data. CNS Drugs. 2011;25(10):829–45.PubMedGoogle Scholar
  21. 21.
    Karlsson P, Dencker E, Nyberg S, More L, More JM. Pharmacokinetics, dopamine D2 and serotonin 5 HT2A receptor occupancy and safety profile of paliperidone ER in healthy subjects. Schizophr Res. 2006;81(Suppl. 1):85–6.Google Scholar
  22. 22.
    Kapur S, Remington G, Jones C, et al. High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: a PET study. Am J Psychiatry. 1996;153:948–50.CrossRefPubMedGoogle Scholar
  23. 23.
    Nordstrom AL, Farde L, Wiesel FA, et al. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry. 1993;33:227–35.CrossRefPubMedGoogle Scholar
  24. 24.
    Nyberg S, Nordstrom AL, Halldin C, Farde L. Positron emission tomography studies on D2 dopamine receptor occupancy and plasma antipsychotic drug levels in man. Int Clin Psychopharmacol. 1995;10(Suppl 3):81–5.PubMedGoogle Scholar
  25. 25.
    Vermeir M, Naessens I, Remmerie B, Mannens G, Hendrickx J, Sterkens P, Talluri K, Boom S, Eerdekens M, van Osselaer N, Cleton A. Absorption, metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans. Drug Metab Dispos. 2008;36(4):769–79.CrossRefPubMedGoogle Scholar
  26. 26.
    Boom S, Thyssen A, Crauwels H, et al. The influence of hepatic impairment on the pharmacokinetics of paliperidone. Int J Clin Pharmacol Ther. 2009;47(10):606–16.CrossRefPubMedGoogle Scholar
  27. 27.
    Savitz AJ, Xu H, Gopal S, Nuamah I, Ravenstijn P, et al. Efficacy and safety of paliperidone palmitate 3-month formulation for patients with schizophrenia: a randomized, multicenter, double-blind, noninferiority study. Int J Neuropsychopharmacol. 2016; 19(7):1–14. doi: 10.1093/ijnp/pyw018.

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Mats O. Magnusson
    • 1
    Email author
  • Mahesh N. Samtani
    • 2
  • Elodie L. Plan
    • 1
  • E. Niclas Jonsson
    • 1
  • Stefaan Rossenu
    • 3
  • An Vermeulen
    • 3
  • Alberto Russu
    • 3
  1. 1.PharmetheusUppsalaSweden
  2. 2.Janssen Research & Development, LLC.RaritanUSA
  3. 3.Janssen Research & Development, A Division of Janssen Pharmaceutica NVBeerseBelgium

Personalised recommendations