Mechanism-Based Pharmacokinetic Modeling of Absorption and Disposition of a Deferoxamine-Based Nanochelator in Rats

Abstract

Deferoxamine (DFO) is an effective FDA-approved iron chelator. However, its use is considerably limited by off-target toxicities and an extremely cumbersome dose regimen with daily infusions. The recent development of a deferoxamine-based nanochelator (DFO-NP) with selective renal excretion has shown promise in ameliorating animal models of iron overload with a substantially improved safety profile. To further the preclinical development of this promising nanochelator and to inform on the feasibility of clinical development, it is necessary to fully characterize the dose and administrationroute-dependent pharmacokinetics and to develop predictive pharmacokinetic (PK) models describing absorption and disposition. Herein, we have evaluated the absorption, distribution, and elimination of DFO-NPs after intravenous and subcutaneous (SC) injection at therapeutically relevant doses in Sprague Dawley rats. We also characterized compartment-based model structures and identified model-based parameters to quantitatively describe the PK of DFO-NPs. Our modeling efforts confirmed that disposition could be described using a three-compartment mamillary model with elimination and saturable reabsorption both occurring from the third compartment. We also determined that absorption was nonlinear and best described by parallel saturable and first-order processes. Finally, we characterized a novel pathway for saturable SC absorption of an ultrasmall organic nanoparticle directly into the systemic circulation, which offers a novel strategy for improving drug exposure for nanotherapeutics.

Application of Allometric Scaling to Nanochelator Pharmacokinetics

“…Comparison of predicted and measured DFO-NP PK after SC administration in CD-1 mice. (A) Structure of compartment-based model with saturable absorption into central compartment, saturable reabsorption from tubular compartment into central compartment, and elimination from tubular compartment . (B) Comparison of the measured and predicted concentration–time profiles after a 3.3 μmol/kg SC dose shows an overestimation of early (<1 h) absorption kinetics.…”

“…Comparison of predicted and measured DFO-NP PK after IV administration in CD-1 mice. (A) Three-compartment mammillary model with saturable reuptake and elimination from tubular compartment . (B) Comparison of measured and predicted concentration–time profile after 0.3 μmol/kg IV dose.…”

“…Traditional allometric scaling was used to calculate the model-based PK parameters for DFO-NPs in both mice and humans using the model structures and model-based parameters determined in rats . In this approach, the PK parameter ( Y ) is related to body weight ( W ) using the power law equation: Y = a W b where a is the allometric coefficient and b is the allometric exponent.…”

“…The outcomes of these studies indicated that DFO-NPs show nonlinear PK after both IV and SC administration, and the results suggested that the disposition of nanochelators was governed by a saturable elimination process. Furthermore, we applied mechanism-based pharmacokinetic modeling to characterize the saturable absorption and disposition of DFO-NPs and to develop a model that accounted for the observed nonlinearity in these processes . While this mechanism-based model adequately and quantitatively described the nonlinear pharmacokinetics of DFO-NPs in rats, its utility of predicting nanochelator PK in other species remained to be evaluated.…”

Recent advances in potential therapeutic targets of ferroptosis‑associated pathways for the treatment of stroke (Review)

“…Similarly, significant research has also been performed on the role of DFO in neurodegenerative diseases (such as diseases that are characterized by neuronal cell death and functional impairments, including Alzheimer's disease, Parkinson's disease and Huntington's disease, which are associated with oxidative stress, abnormal neurodevelopment and protein aggregation) ( 153 ). Upon reviewing the literature, DFO has been shown to reduce the level of cell death through reducing free radicals ( 165 ), and to promote wound healing and healing in diabetic patients ( 166 ), although due to the potential toxicity of DFO itself ( 167 ), the research remains only at an early stage ( 160 ). In addition, animal experiments were used to demonstrate that the treatment of mice with DFO, wherein the aging process was simulated, led to a marked alleviation of the occurrence of ferroptosis, with the consequent inhibition of the increase of age spots in mice due to iron overload, thereby achieving the desired protective effect of delaying aging ( 168 ).…”