2010 - Berlin - Germany

PAGE 2010: Applications- CNS
Mahesh Samtani

Switching to Paliperidone Palmitate[1,2] from Other Depot Antipsychotics: Guidance Based on Pharmacokinetic Simulations

Mahesh N. Samtani (1); Srihari Gopal (1); Jennifer Kern Sliwa (2); J. Thomas Haskins (2); Larry Alphs (2); Kim Stuyckens (3); An Vermeulen (3).

(1) Johnson & Johnson Pharmaceutical Research & Development, L.L.C., NJ, USA; (2) Ortho-McNeil Janssen Scientific Affairs, L.L.C, NJ, USA; (3) Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica N.V., Beerse, Belgium

Objective: Population PK models have been developed for paliperidone palmitate (PP) and risperidone long-acting injection (RLAI) based on data from schizophrenia subjects. The final models, including significant subject covariates, were used as simulation tools to investigate dosing strategies for patients switching from other depot antipsychotics to PP.

Methods: A 1-compartment model with parallel zero/1st order absorption described the PK of PP. A 1-compartment model with 3 parallel absorption pathways described the PK of RLAI. Covariates of interest were obtained by resampling subject covariates available in the PK database for PP. To evaluate outcomes of simulation scenarios, the population median and 90% prediction interval of the simulated concentration vs. time profiles were plotted together. In addition, a literature search was also performed to understand the PK characteristics of other depot injectable antipsychotics.

Results: The literature search results showed that, for other depot antipsychotics, the administration interval is in the range of 1-2 half-lives for each product. This indicates that at the time of switching to PP (instead of the scheduled injection of the previous depot antipsychotic) there will be sustained therapeutic levels of the prior drug in the systemic circulation. Given that significant levels of the previous antipsychotic would be present in the systematic circulation, there would be no need to administer the second initiation dose of PP on Day 8, which is otherwise needed to quickly elevate concentrations to therapeutic levels. This concept of not needing a Day 8 loading dose when switching to PP from other depot antipsychotics was illustrated through simulations using RLAI, which contains the active moiety of PP. Plasma concentrations were simulated with PP injection, 2 weeks after the last RLAI injection followed by monthly injections of PP. The results indicate that drug levels are maintained close to steady-state right after the switch. During the switch, neither the Day 8 injection nor oral supplementation is necessary. Thus this simple strategy of (a) Initiating PP instead of the regularly scheduled injection of the previous depot antipsychotic; and (b) Following up with monthly injections of PP, is considered to be both convenient and practical.

Conclusions: These PK simulation scenarios provide important guidance on PP dosing in patients previously treated with depot antipsychotics.

[1] FDA Approves Once-Monthly Paliperidone Palmitate Injection for Treating Schizophrenia. Medscape Medical News [2009]. http://www.medscape.com/viewarticle/706977
[2] Janssen-Cilag submits MAA to the European Medicines Agency for paliperidone palmitate. The Medical News [2009]. http://www.news-medical.net/news/20091204/Janssen-Cilag-submits-MAA-to-the-European-Medicines-Agency-for-paliperidone-palmitate.aspx

Reference: PAGE 19 (2010) Abstr 1839 [www.page-meeting.org/?abstract=1839]
Poster: Applications- CNS
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