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
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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.
KeywordsExtended Release Paliperidone Population Pharmacokinetic Model Paliperidone Palmitate Mild Renal Impairment
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.
- 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
- 5.US label of INVEGA® SUSTENNA® (Revised 01/2016). Available at: http://www.invegasustenna.com/important-product-information. Accessed 10 May 2016.
- 6.EU label of TREVICTA® (last updated on eMC 09/2016). Available at https://www.medicines.org.uk/emc/medicine/32050. Accessed 16 Dec 2016.
- 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.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.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. http://www.page-meeting.org/?abstract=3408.
- 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
- 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.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.Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ. NONMEM Users Guides. 1989 Icon development solutions, Ellicott City, Maryland.Google Scholar
- 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 http://www.R-project.org. Accessed 18 Jan 2016.
- 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
- 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.