Research tools for extrapolating the disposition and pharmacokinetics of nanomaterials from preclinical animals to humans

Abstract

A critical step in the translational science of nanomaterials from preclinical animal studies to humans is the comprehensive investigation of their disposition (or ADME) and pharmacokinetic behaviours. Disposition and pharmacokinetic data are ideally collected in different animal species (rodent and nonrodent), at different dose levels, and following multiple administrations. These data are used to assess the systemic exposure and effect to nanomaterials, primary determinants of their potential toxicity and therapeutic efficacy. At toxic doses in animal models, pharmacokinetic (termed toxicokinetic) data are related to toxicologic findings that inform the design of nonclinical toxicity studies and contribute to the determination of the maximum recommended starting dose in clinical phase 1 trials. Nanomaterials present a unique challenge for disposition and pharmacokinetic investigations owing to their prolonged circulation times, nonlinear pharmacokinetic profiles, and their extensive distribution into tissues. Predictive relationships between nanomaterial physicochemical properties and behaviours in vivo are lacking and are confounded by anatomical, physiological, and immunological differences amongst preclinical animal models and humans. These challenges are poorly understood and frequently overlooked by investigators, leading to inaccurate assumptions of disposition, pharmacokinetic, and toxicokinetics profiles across species that can have profoundly detrimental impacts for nonclinical toxicity studies and clinical phase 1 trials. Herein are highlighted two research tools for analysing and interpreting disposition and pharmacokinetic data from multiple species and for extrapolating this data accurately in humans. Empirical methodologies and mechanistic mathematical modelling approaches are discussed with emphasis placed on important considerations and caveats for representing nanomaterials, such as the importance of integrating physiological variables associated with the mononuclear phagocyte system (MPS) into extrapolation methods for nanomaterials. The application of these tools will be examined in recent examples of investigational and clinically approved nanomaterials. Finally, strategies for applying these extrapolation tools in a complementary manner to perform dose predictions and in silico toxicity assessments in humans will be explained. A greater familiarity with the available tools and prior experiences of extrapolating nanomaterial disposition and pharmacokinetics from preclinical animal models to humans will hopefully result in a more straightforward roadmap for the clinical translation of promising nanomaterials.

Antitumor and Radiosensitizing Effects of Zinc Oxide-Caffeic Acid Nanoparticles against Solid Ehrlich Carcinoma in Female Mice

“…115 It also provides a more conservative dose estimate, especially for nanomaterials. 116 Generally, the body surface area seems to have a good correlation among species with several parameters including oxygen utilization, caloric expenditure, basal metabolism, blood volume, and circulating plasma protein. 37,117 Valic and Zheng 116 mentioned that the clinical starting dose may be determined by dividing the estimated human equivalent dose (HED) of the rodent by a safety factor with a default value of 10.…”

“…116 Generally, the body surface area seems to have a good correlation among species with several parameters including oxygen utilization, caloric expenditure, basal metabolism, blood volume, and circulating plasma protein. 37,117 Valic and Zheng 116 mentioned that the clinical starting dose may be determined by dividing the estimated human equivalent dose (HED) of the rodent by a safety factor with a default value of 10. The safety factor allows variability in extrapolating from animal toxicity studies in humans resulting from uncertainties due to enhanced sensitivity to pharmacologic activity in humans versus animals, difficulties in detecting certain pathologies in animals (eg, headache, myalgia, and mental disturbances), differences in receptor densities or affinities, and unexpected toxicities.…”

Assessment of the dose-dependent biochemical and cytotoxicity of zein-coated MgO nanowires in male and female albino rats

“…It was stated that the dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology were understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers [ 54 , 55 ]. Also, it was reported that the extrapolating nanomaterials disposition and pharmacokinetics from preclinical animal models to humans will hopefully result in a more straightforward roadmap for the clinical translation of promising nanomaterials [ 56 ]. In this concern, several equations were used to calculate the human equivalent dose (HED); most commonly was that related to body weight [ 55 ] as follows: …”

Bictegravir Plus Tenofovir Alafenamide Nanoformulation as a Long-Acting Pre-Exposure Prophylaxis Regimen: Application of Modeling to Design Non-Human Primate Pharmacokinetic Experiments

“…In bringing forward nBIC-TAF to non-human primates (NHP) testing, as the best animal model for HIV therapy/PrEP preclinical assessments, many unknowns surround the choice of the NHP regimen. Nanoformulated drugs have a high degree of pharmacokinetic unpredictability when scaled from smaller to higher species, and therefore it can be inappropriate to use standard interspecies scaling rules for nanoformulated drugs (Valic and Zheng, 2019). Additionally, NHP experiments are costly and beg ethical concerns, thus doseescalation assessments in NHP could become burdensome.…”