Guidelines for the experimental design of pharmacokinetic studies with nanomaterials in preclinical animal models

A shared feature in the value proposition of every nanomaterial-based drug delivery systems is the desirable improvement in the disposition (or ADME) and pharmacokinetic profiles of the encapsulated drug being delivered. Remarkable progress has been made towards understanding the complex and multifactorial relationships between pharmacokinetic profiles and nanomaterial physicochemical properties, biological interactions, species physiology, etc. These advances have fuelled the rational design of numerous nanomaterials with long-circulation times and improved tissue accumulation (e.g., in tumours). Unfortunately, a central weakness in many of these research efforts has been the inconsistent and insufficient characterisation of the pharmacokinetic profiles of nanomaterials in scientific reporting—a problem affecting the majoirty of of contemporary nanomaterials literature and innovative nanomaterials in early stages of preclinical development especially. Given the significant role of pharmacokinetic assessments to serve as guideposts for deciding whether to continue with the preclinical development and clinical translation of drug delivery systems, the prevalence of poor pharmacokinetic characterisations in nanomaterials research is particularly alarming. A conspicuous problem in many reports is the inappropriate selection of experimental designs and methodologies for studying nanomaterial pharmacokinetics, the consequences of which are increased uncertainty over the accurate interpretation of reported pharmacokinetic data and diminished experimental reproducibility throughout the field. Thus, there is renewed interest in the establishment of consistent and comprehensive strategies for designing preclinical experiments to assess the pharmacokinetics of nanomaterials with diverse physicochemical properties. Towards this end, herein are proposed simple guidelines for the experimental design of pharmacokinetic studies with nanomaterials drawn from the best research practices, principle strategies, and important considerations used in industry for collecting pharmacokinetic data in preclinical animal models. Specifically, key experimental design factors in these studies are identified and examined in the context of nanomaterials for optimality, including blood sampling strategy and technique, sample allocation and sampling time window, test species selection, experimental sources of pharmacokinetic variability, etc. Methods for noninvasive imaging-derived pharma