Clinical Pharmacokinetics

, Volume 56, Issue 4, pp 421–433 | Cite as

Population Pharmacokinetics of a Novel Once-Every 3 Months Intramuscular Formulation of Paliperidone Palmitate in Patients with Schizophrenia

  • Mats O. Magnusson
  • Mahesh N. Samtani
  • Elodie L. Plan
  • E. Niclas Jonsson
  • Stefaan Rossenu
  • An Vermeulen
  • Alberto Russu
Original Research Article



Our objective was to characterize the population pharmacokinetics of paliperidone after intramuscular administration of its long-acting 3-month formulation palmitate ester at various doses and at different injection sites (deltoid and gluteal muscles).


This retrospective analysis included pooled data from 651 subjects from one phase I study (single injection of the 3-month formulation) and one phase III study (multiple injections of both 1- and 3-month formulations). A total of 8990 pharmacokinetic samples with valid concentration time points were available for this analysis. Nonlinear mixed-effects modelling of the pooled data was conducted using NONMEM software. Knowledge from a previously developed 1-month formulation model was used as a starting point to build the 3-month formulation model.


The final model describing the plasma concentrations after administration of the 3-month formulation was a one-compartment model with first-order elimination and two saturable absorption processes (rapid and slow). The apparent volume of distribution estimated for the 3-month formulation was not the same as for the previously modelled 1-month formulation. Apparent clearance (CL), apparent volume of distribution (V), and fraction of the absorbed dose (F3) were estimated to be 3.84 l/h, 1960 L, and 20.9 %. For slow absorption, the maximum absorption rate constant (k a1 max), amount of paliperidone at the absorption site when half of the maximum absorption rate was achieved (k amt1 50), and Hill factor (γ) were estimated to be 90.4 µg/h, 120 mg, and 1.44, respectively. For rapid absorption, the maximum absorption rate constant (k a3 max) and amount of paliperidone at the absorption site when half of the maximum absorption rate was achieved (k amt3 50) were estimated to be 164 µg/h and 21.4 mg, respectively.


The final model with two saturable absorption processes provided a good description of the pharmacokinetic characteristics of paliperidone after intramuscular administration of its long-acting 3-month formulation palmitate ester. In addition to the structural covariates (creatinine clearance on CL, body mass index on V, and injection volume on both absorption rates), injection site and sex were identified as covariates on k a max of the slow absorption process (k a1 max).

Clinical trial registration numbers: NCT01559272, NCT01529515, and NCT01515423


Paliperidone Absorption Parameter Population Pharmacokinetic Model Objective Function Value Visual Predictive Check 
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 thank Tinka Tuinstra PhD, an employee of AUTHOR! et al. BV, for her medical writing assistance.

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.

Supplementary material

40262_2016_459_MOESM1_ESM.docx (9.6 mb)
Supplementary material 1 (DOCX 9856 kb)


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Mats O. Magnusson
    • 1
  • 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, LLCRaritanUSA
  3. 3.Janssen Research & Development, A Division of Janssen Pharmaceutica NVBeerseBelgium

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