The effect of macrophage and angiogenesis inhibition on the drug release and absorption from an intramuscular sustained-release paliperidone palmitate suspension

Abstract

The intramuscular (IM) administration of long-acting injectable (LAI) aqueous nano-/microsuspensions elicits a chronic granulomatous injection site reaction, which recently has been hypothesized to drive the (pro)drug dissolution and systemic absorption resulting in flip-flop pharmacokinetics. The goal of this mechanistic study was to investigate the effects of the local macrophage infiltration and angiogenesis on the systemic drug exposure following a single IM administration of a paliperidone palmitate (PP) LAI nano-/microsuspension in the rat. Liposomal clodronate (CLO) and sunitinib (SNT) were co-administered to inhibit the depot infiltration and nano-/microparticle phagocytosis by macrophages, and the neovascularization of the depot, respectively. Semi-quantitative histopathology of the IM administration sites at day 1, 3, 7, 14, 21 and 28 after dosing with PP-LAI illustrated that CLO significantly decreased the rate and extent of the granulomatous inflammatory reaction. The macrophage infiltration was slowed down, but only partially suppressed by CLO and this translated in paliperidone (PAL) plasma concentration-time profiles that resembled those observed upon injection of PP-LAI only, albeit with a lower PAL input rate and delayed maximum plasma concentration (CMAX). Conversely, SNT treatment completely suppressed the granulomatous reaction, besides effectively inhibiting the neovascularization of the PP-LAI depot. This resulted in an even slower systemic PAL input with delayed and lower maximum PAL CMAX. The reduced PP-LAI lymph node retention after CLO and SNT treatment, as well as pharmacokinetic drug-drug interactions were rejected as possible sources of the observed pharmacokinetic differences. The biphasic PAL plasma concentration-time profiles could best be described by an open first-order disposition model with parallel fast (first-order) and slow (sequential zero-first-order) absorption. The correlation of the pharmacokinetic data with the histopathological findings indicated that the macrophage infiltration, with subsequent phagocytosis of an important fraction of the PP-LAI dose, actively contributed to the observed PAL plasma exposures by promoting the prodrug dissolution and conversion to the active. An initial fast PP dissolution of individual nano-/microcrystals present in the interstitium was followed by a second, slower, but dominating input process that was driven by the PAL formation rate in the infiltrated portions of the LAI depot. The present work provides new fundamental insights into the influence of the local tissue response to IM LAI (pro)drug suspensions on the systemic drug exposure. This knowledge might support the future development of predictive in vitro and in silico models, which could help guide the LAI formulation design.

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

“…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. The injection site reaction, and macrophages in particular, was found to contribute to the slow drug release, hence, modulating the prolonged pharmacokinetics associated with these LAI drug delivery systems (Darville, van Heerden, Mariën, et al 2016). Similar conclusions on the contribution of the formation of intracellular drug depots in monocyte-derived macrophages to the (very) long-acting properties of surface-modified antiretroviral drug nanocrystals were recently drawn by another group (Gnanadhas et al 2017;Edagwa et al 2017).…”

“…Also, the differences in plasma concentration versus time profiles—which are likely to be attributable to differences in i.m. drug release rates—appeared to be restricted to the first 7 to 14 days after administration, while from day 14 onward, a convergence of the plasma concentrations and near parallel first-order decline rates (which in case of slow-release parenteral drug delivery often represent the slow systemic drug absorption rather than the drug clearance from the plasma compartment) were observed (Darville, van Heerden, Mariën, et al 2016). The similar formulation behavior after day 14 correlates with the increased similarity in severity and nature of the inflammatory response across all groups from day 14 onward.…”

Human tissue-engineered skeletal muscle: a novel 3D in vitro model for drug disposition and toxicity after intramuscular injection

“…A suspension for injection represents an interesting dosage form for certain drugs. For example, a slow-release version of antipsychotic drugs such as paliperidone may decrease the number of individual injections needed, leading to a better therapy compliance 56 . Furthermore we could clearly show the utility of our 3D model to follow release kinetics over time, in constrast to a 2D cell culture model (Fig.…”

Thiolated Chitosan Masked Polymeric Microspheres with Incorporated Mesocellular Silica Foam (MCF) for Intranasal Delivery of Paliperidone

“…Also, large amounts of crystalline paliperidone-LAI particles were found within the infiltrating macrophages, supporting the hypothesis that the sudden drop in dissolution rate of the drug and its potential absorption lead to accumulation of the drug in macrophages. The same group investigated the co-administration of liposomal clodronate and sunitinib in order to inhibit the depot infiltration and nano-/microparticle phagocytosis by macrophages, and the neovascularization of the depot, respectively [22].…”