Erno van Schaick (1), Nicolas Darville (2), Philippe Jacqmin (3), Stefaan Rossenu (2), An Vermeulen (2)
(1) Calvagone, Lyon, France, (2) Janssen R&D, a division of Janssen Pharmaceutica NV, Beerse, Belgium, (3) MnS, Dinant, Belgium
Objectives: The objective of the present work was to develop a mechanism-based model that can predict the in vivo pharmacokinetic profile of intramuscular long-acting injectable (LAI) microsuspensions of paliperidone palmitate (PP) in rats, based on formulation characteristic, PK parameters of the active compound paliperidone and time-dependent histological parameters related to the local tissue response after intramuscular injection of depot formulations.
Methods: The in vivo release rate of intramuscular long-acting injectable PP microsuspensions in rats was described by a mechanism-based model that consisted of two main parts:
- One part describing drug release based on in vitro performance properties and formulation characteristics such as the intrinsic dissolution rate and particle size distribution.
- A second part, where drug release is orchestrated by the local chronic inflammatory reaction with macrophage infiltration.
Intramuscular injections of clinical 1-month (Xeplion®) and 3-month (Trevicta®) depot formulations of paliperidone palmitate were evaluated in rats. These crystalline suspensions were characterized for their particle size distribution and median particle diameter. Histopathological evaluations of the injection site provided rate constants for infiltration of macrophages into the drug depot, as part of the natural foreign-body reaction to the injection[1,2]. The subsequent release rate of paliperidone from macrophage-encapsulated drug particles was evaluated in an in vitro macrophage-based particle uptake and drug release model. Plasma concentration-time profiles of paliperidone in rats following a single intramuscular injection of 20 mgEq./kg of the 1-month depot and 70 mgEq./kg of the 3-month depot were assessed over a period of 3-12 weeks post-dose. Intramuscular and intravenous administration of a paliperidone immediate release formulation in rats was used to obtain the disposition kinetics of the active compound. The mechanistic model was implemented in Simulo[3] and used to elucidate the key elements that define the observed slow-release kinetics of paliperidone.
Results: Typically, the paliperidone concentration-time profiles in rats were multi-phasic with an initial, short-lasting peak in plasma concentrations occurring within 24-hours, followed by a slow increase in levels with maximum concentrations occurring at 7 to 14 days post injection. The initial fast paliperidone release during the first 24-hours post injection was shown to be mainly driven by dissolution of paliperidone palmitate at the surface of the particles. Simulations indicated that this dissolution driven process occurred slower in vivo and lasted for a relatively short time. The process of the foreign body reaction after injection was shown to be an important driver for the slow release characteristics of the injected PP suspension. The rate of macrophage infiltration of the depot (half-life of infiltration of 3.3-4.4 days for the 1-month depot and 6.1 days for the 3-month depot) and the observed extensive phagocytosis of drug particles[1] provided rate constants for the macrophage uptake. The macrophage infiltration/uptake and release rates were the driving parameters for the observed slow appearance and slow decline of paliperidone in plasma following intramuscular administration of the PP long-acting injectable suspensions.
Conclusions: The present work supports the development of a translational mechanistic model that potentially can predict systemic exposure of novel intramuscular LAI nano-/microsuspensions based on in vitro and in vivo design characteristics and may, as such, support future rational formulation development.
References:
[1] Darville et al. Intramuscular administration of paliperidone palmitate extended-release injectable microsuspension induces a subclinical inflammatory reaction modulating the pharmacokinetics in rats. J. Pharm. Sci. (2014), 103(7): 2072–2087.
[2] Darville et al. Modeling the time course of the tissue responses to intramuscular long-acting paliperidone palmitate nano-/microcrystals and polystyrene microspheres in the rat. Toxicol. Pathol. (2015), 44(2): 189–210
[3] Simulo by SGS Exprimo, version 7.1.2
Reference: PAGE 27 (2018) Abstr 8705 [www.page-meeting.org/?abstract=8705]
Poster: Drug/Disease Modelling - Absorption & PBPK