title: Modeling the Time Course of the Tissue Responses to Intramuscular Long-acting Paliperidone Palmitate Nano-/Microcrystals and Polystyrene Microspheres in the Rat.
abstract: Long-acting injectable (LAI) drug suspensions consist of drug nano-/microcrystals suspended in an aqueous vehicle and enable prolonged therapeutic drug exposure up to several months. The examination of injection site reactions (ISRs) to the intramuscular (IM) injection of LAI suspensions is relevant not only from a safety perspective but also for the understanding of the pharmacokinetics. The aim of this study was to perform a multilevel temporal characterization of the local and lymphatic histopathological/immunological alterations triggered by the IM injection of an LAI paliperidone palmitate suspension and an analog polystyrene suspension in rats and identify critical time points and parameters with regard to the host response. The ISRs showed a moderate to marked chronic granulomatous inflammation, which was mediated by multiple cyto-/chemokines, including interleukin-1β, monocyte Chemoattractant Protein-1, and vascular endothelial growth factor. Lymphatic uptake and lymph node retention of nano-/microparticles were observed, but the contribution to the drug absorption was negligible. A simple image analysis procedure and empirical model were proposed for the accurate evaluation of the depot geometry, cell infiltration, and vascularization. This study was designed as a reference for the evaluation and comparison of future LAIs and to support the mechanistic modeling of the formulation-physiology interplay regulating the drug absorption from LAIs.
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, Leuven, Belgium Model Based Drug Development, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium These authors contributed equally.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Darville
authors.affiliation: Preclinical Development and Safety, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium These authors contributed equally mvheerde@its.jnj.com.
authors.forename: Marjolein
authors.initials: M
authors.lastname: van Heerden
authors.affiliation: Preclinical Development and Safety, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Erkens
authors.affiliation: Preclinical Development and Safety, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: De Jonghe
authors.affiliation: Preclinical Development and Safety, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vynckier
authors.affiliation: Preclinical Development and Safety, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: De Meulder
authors.affiliation: Model Based Drug Development, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.affiliation: Preclinical Development and Safety, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sterkens
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Van den Mooter
mesh_terms: D000818:Animals; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D003692:Delayed-Action Preparations; D007273:Injections, Intramuscular; D008198:Lymph Nodes / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008863:Microspheres; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage*; D009928:Organ Specificity / Q000187:drug effects; D000068882:Paliperidone Palmitate / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011137:Polystyrenes / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism
chemical_list: D016207:Cytokines; D003692:Delayed-Action Preparations; D011137:Polystyrenes; D042461:Vascular Endothelial Growth Factor A; D000068882:Paliperidone Palmitate
keywords: cytokines; inflammation; intramuscular; long-acting injectable; nano-/microparticles; paliperidone palmitate; quantitative histology