Population Pharmacokinetic Simulations of Two Paliperidone Palmitate Formulations
Mats O. Magnusson (1)*; Mahesh N. Samtani (2)*; Elodie L. Plan (1); E. Niclas Jonsson (1); Stefaan Rossenu (3); An Vermeulen (3) (*equal contribution)
(1) Pharmetheus, Uppsala, Sweden; (2) Johnson & Johnson Pharmaceutical Research & Development, L.L.C., NJ, USA; (3) Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutical N.V., Beerse, Belgium.
Background: Population pharmacokinetic (PK) models have been developed for paliperidone palmitate 1 and 3-month formulations (PP1M and PP3M).
Objective: To investigate dosing strategies for PP3M and to explore the impact of selected covariates using the final models, including significant subject covariates, as simulation tools.
Methods: A 1-compartment model with parallel zero and first-order absorption describing the PK of PP1M  and a 1-compartment model with 2 saturable absorption processes describing the PK of PP3M  were used for simulations in R 3.0.2 . Covariates of interest  were obtained by resampling subject covariates available in the PK database for PP1M and PP3M in order to keep realistic correlations across the covariates. Simulation scenarios with varying dosing times and covariate values were generated. The population median and 90% prediction interval of the simulated concentration-time profiles were plotted for simulation outcomes evaluation.
Results: PP3M administered every 12 weeks, at doses that are a 3.5-fold multiple of the corresponding PP1M dose, appears to result in paliperidone exposures similar to those obtained with doses of PP1M every 4 weeks. Paliperidone PK, when administered as PP3M, was not significantly altered in subjects of different sex or using the deltoid or the gluteal injection site. Once stabilized on treatment with PP3M, trough paliperidone plasma concentrations were similar in subjects with different BMI. Furthermore simulations showed that subjects with mild renal impairment were expected to have higher exposures, however dose adjustment is not required for PP3M since it is done when initiating PP1M. Peak plasma concentrations for a typical patient were achieved within 30-33 days after a single PP3M injection over the dose range of 175-525 mg eq. The PK of paliperidone palmitate was dose-proportional for overall exposure and appeared to be dose-proportional for Cmax over a dose range of 175-525 mg eq. At steady-state the PP3M peak-to-trough ratio was 1.6-1.7 following gluteal and deltoid administrations, which is similar to the peak-to-trough ratios following deltoid PP1M injections. The apparent half-life of the PP3M formulation was in the range of 84-95 days following a deltoid injection and 118-139 days following a gluteal injection.
Conclusion: The explored PK simulation scenarios provided important guidance on PP3M dosing in schizophrenic patients and supported a once every 3 months injection cycle.
 Samtani MN, Gopal S, Gassmann-Mayer C, Alphs, L, and Palumbo J M; Dosing and switching strategies for paliperidone palmitate: based on population pharmacokinetic modelling and clinical trial data. CNS Drugs, 25(10):829–845, Oct 2011
 Magnusson MO, Samtani MN; Plan EL, Jonsson EN, Rossenu S, Vermeulen A; Population Pharmacokinetic Modeling of Paliperidone Palmitate 3-Month Formulation. PAGE (2015)
 R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0.