Population Pharmacokinetic Modeling of Paliperidone Palmitate 3-Month Formulation
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: A new paliperidone palmitate 3-month formulation (PP3M) has been developed aiming at retained efficacy compared to the marketed paliperidone 1-month formulation (PP1M).
Objectives: To characterize the dose-concentration-time relationship of paliperidone following administration of PP3M.
Methods: Pharmacokinetic (PK) data were obtained from 1 single-dose Phase 1 study (R092670-PSY-1005) and 1 repeated-dose Phase 3 study (R092670-PSY-3012). Plasma concentrations were analyzed using non-linear mixed-effects PK modeling implemented in NONMEM 7.3.0 [1]. A previously developed PK model for PP1M was used to describe the PK of paliperidone after PP1M administration [2] for patients in Study R092670-PSY-3012 who were treated with PP1M for 4 months before PP3M treatment commenced. The final model for PP3M was based on 8990 PK samples from 651 subjects.
Results: The PP1M PK model provided an adequate description of the PP1M data when the model parameters were associated with uncertainty [3] (10%). A 1-compartment model with 2 saturable absorption processes (slow and fast) was developed to characterize the PK of paliperidone after PP3M administration. The covariates in the PP3M model were creatinine clearance on clearance, BMI on volume of distribution, injection volume on the absorption rate, and injection site and sex on the maximal absorption rate for the slow saturable absorption process.
Conclusions: The PK characteristics of paliperidone when administered as a single and multiple injections of PP3M were well captured in a population PK model for PP3M.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] 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.
[3] Gisleskog, P. O., Karlsson, M. O., and Beal, S. L. Use of prior information to stabilize a population data analysis. J Pharmacokinet Pharmacodyn, 29(5-6):473–505, Dec 2002.
