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-1b, 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.

Pharmacokinetics, safety and tolerability of long‐acting parenteral intramuscular injection formulations of doravirine

“…A biphasic release profile differs from the more commonly observed initial peak followed by steady release; the mechanism behind the release profile observed in our study is unknown and may be related to unique absorption or release mechanisms. One such hypothesis was studied systematically by Darville et al with paliperidone palmitate nano/microsuspensions, where they demonstrated that key determinants of release in vivo were depot morphology, size, shape and local inflammatory response kinetics 24,25 …”

The Current Landscape of Novel Formulations and the Role of Mathematical Modeling in Their Development

“…61,85,86 Darville et al have observed the formation of granuloma, macrophage infiltration, and inflammation at the depot site post-IM injection of LA paliperidone palmitate, describing a multifactorial scenario at that site of injection. 87 Following administration of an injectable LA formulation, the removal of the nanoformulation and the discontinuation of treatment would require surgical expertise, if any complexities arise. To address this problem, recently, there is a high demand to modify existing injectable contraceptives to implants, namely, long-acting reversible contraceptives to ease the removal process in case of complications.…”

“…For example, for IM injectable LA formulations, only a relatively limited understanding of local tissue mechanisms influencing the drug release from the site of administration is currently available, and initial studies have indicated multifactorial scenarios in which chemical degradation, neoangiogenesis, and inflammation interact in the definition of drug absorption. 87 Moreover, PBPK models can support the simulation of drug distribution in animals defining opportunities to refine, replace, and reduce the use of preclinical species in the investigation of novel formulation. The coupling of animal and human PBPK models is an exciting prospect to inform the bridging of PK and therefore streamline the development of novel formulations.…”

Comparison of the Local Tolerability to 5 Long-acting Drug Nanosuspensions with Different Stabilizing Excipients, Following a Single Intramuscular Administration in the Rat

“…Therefore, a detailed characterization of the histopathological response to i.m. injections of LAI nanosuspensions containing different stabilizers is essential, not only in the assessment of the tolerability and safety profile of the drug product (including the functional excipients) but also to obtain fundamental insights in the processes contributing to the pharmacokinetics of LAI formulations (Darville, van Heerden, Erkens, et al 2016). This was exemplified in a series of studies conducted by our group, which demonstrated that the granulomatous inflammatory reaction occurring upon i.m.…”

“…The gradual yet extensive infiltration of CD68 þ macrophages within the formulation depot formed at the i.m. injection site was accompanied by increasing amounts of LAI formulation being phagocytosed over time (Darville, van Heerden, Erkens, et al 2016). This process of gradual uptake by macrophages and the intracellular relocation of large portions of the LAI dose meant that the intramacrophagic space became the primary site of drug dissolution and release.…”