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

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.