Application of Allometric Scaling to Nanochelator Pharmacokinetics

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 involving daily infusions. The recent development of a deferoxamine-based nanochelator (DFO-NP) with selective renal excretion has shown promise in ameliorating iron overload and associated physiological complications in rodent models with a substantially improved safety profile. While the dose- and administration route-dependent pharmacokinetics (PK) of DFO-NPs have been recently characterized, the optimized PK model was not validated, and the prior studies did not directly address the clinical translatability of DFO-NPs into humans. In the present work, these gaps were addressed by applying allometric scaling of DFO-NP PK in rats to predict those in mice and humans. First, this approach predicted serum concentration–time profiles of DFO-NPs, which were similar to those experimentally measured in mice, validating the nonlinear disposition and absorption models for DFO-NPs across the species. Subsequently, we explored the utility of allometric scaling by predicting the PK profile of DFO-NPs in humans under clinically relevant dosing schemes. These in silico efforts demonstrated that the novel nanochelator is expected to improve the PK of DFO when compared to standard infusion regimens of native DFO. Moreover, reasonable formulation strategies were identified and discussed for both early clinical development and more sophisticated formulation development.

Advances in Physiologically Based Pharmacokinetic (PBPK) Modeling of Nanomaterials

“…This method predicted the serum concentration–time profile of DFO-NPs to be very close to the experimentally determined values in mice, and nonlinear disposition and absorption models were validated for DFO-NPs for multiple doses across the species . The pharmacokinetic profile of DFO-NPs in humans was predicted by carrying out allometric scaling by applying clinically meaningful dosages, and pharmacokinetic simulations were carried out demonstrating improved pharmacokinetics by a nanochelator compared to PK profiles after typical infusion protocols of DFO . However, some limitations have been reported such as the requirement of setting up DFO-NP-specific allometric exponents for all the mechanisms incorporated in the pharmacokinetic model to increase the accuracy of the prediction .…”

“…However, since preclinical data from at least three species were required to predict the exponent of powers in model scaling to determine the clearance by regression analysis, better predictions can be obtained when the number of species is increased in the model for TNF-gold nanoparticles. A study carried out a simple allometric scaling approach to deferoxamine-based nanochelator (DFO-NP) in rats to predict pharmacokinetic parameters in mice and humans . This method predicted the serum concentration–time profile of DFO-NPs to be very close to the experimentally determined values in mice, and nonlinear disposition and absorption models were validated for DFO-NPs for multiple doses across the species .…”

“…A study carried out a simple allometric scaling approach to deferoxamine-based nanochelator (DFO-NP) in rats to predict pharmacokinetic parameters in mice and humans . This method predicted the serum concentration–time profile of DFO-NPs to be very close to the experimentally determined values in mice, and nonlinear disposition and absorption models were validated for DFO-NPs for multiple doses across the species . The pharmacokinetic profile of DFO-NPs in humans was predicted by carrying out allometric scaling by applying clinically meaningful dosages, and pharmacokinetic simulations were carried out demonstrating improved pharmacokinetics by a nanochelator compared to PK profiles after typical infusion protocols of DFO .…”

“…The pharmacokinetic profile of DFO-NPs in humans was predicted by carrying out allometric scaling by applying clinically meaningful dosages, and pharmacokinetic simulations were carried out demonstrating improved pharmacokinetics by a nanochelator compared to PK profiles after typical infusion protocols of DFO . However, some limitations have been reported such as the requirement of setting up DFO-NP-specific allometric exponents for all the mechanisms incorporated in the pharmacokinetic model to increase the accuracy of the prediction . Another constraint in the model was explained as using simple allometry in the scaling of nonlinear pharmacokinetics may be unreliable …”

“…However, some limitations have been reported such as the requirement of setting up DFO-NP-specific allometric exponents for all the mechanisms incorporated in the pharmacokinetic model to increase the accuracy of the prediction . Another constraint in the model was explained as using simple allometry in the scaling of nonlinear pharmacokinetics may be unreliable …”