When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics?

Abstract

Nanoformulations have become important tools for modifying drug disposition, be it from the perspective of enabling prolonged drug release, protecting the drug molecule from metabolism, or achieving targeted delivery. When examining the in vivo pharmacokinetic properties of these formulations, most investigations either focus on systemic concentrations of total (encapsulated plus unencapsulated) drug, or concentrations of encapsulated and unencapsulated drug. However, it is rare to find studies that differentiate between protein-bound and unbound (free) forms of the unencapsulated drug. In light of the unique attributes of these formulations, we cannot simply assume it appropriate to rely upon the protein-binding properties of the traditionally formulated or legacy drug when trying to define the pharmacokinetic or pharmacokinetic/pharmacodynamic characteristics of these nanoformulations. Therefore, this commentary explores reasons why it is important to consider not only unencapsulated drug, but also the portion of unencapsulated drug that is not bound to plasma proteins. Specifically, we highlight those situations when it may be necessary to include measurement of unencapsulated, unbound drug concentrations as part of the nanoformulation pharmacokinetic evaluation.

Mapping of the available standards against the regulatory needs for nanomedicines

“…These properties need to be evaluated in a physiologically relevant medium or in vivo in order to assess the safety and efficacy of the nanomedicine and to compare the pharmacokinetics (PKs) of the free drug with that of the nanoformulation. The possibility that the free drug is in equilibrium with the protein‐bound drug and as well with the drug in its nanoformulation adds an additional challenge to this task (Stern, Martinez, & Stevens, ). When targeting the diseased tissues, the carrier should ideally deliver the drug directly to the diseased cells.…”

“…Thus, free drug in blood is a sign of imperfect targeting. It appears that the conceptual differences between traditional pharmacology and nanopharmacology even require a consensus on a new terminology to be used (Stern et al, ).…”

Equivalence of complex drug products: advances in and challenges for current regulatory frameworks

“…However, novel techniques for evaluating complex drug similarity are becoming available at a rapid pace. For example, advanced methods recently developed by the Nanotechnology Characterization Laboratory may accelerate the understanding of which parameters are part of the critical attributes and thereby potentially speed up development of follow‐on versions of nanoparticle‐based products.…”

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

“…[111][112][113] Classical PK study is aimed to measure the concentration of drugs in almost all tissues over a period of time after the administration of the drugs until the phase of elimination. The PK of the free drug is largely altered by the nanoparticle at least until it is released from the nanoparticle, whereas the nanoparticle's PK is mainly dictated by their physicochemical properties, such as size, charge, and surface chemistry.…”

“…Therefore, for the nanomedicines' formulation the PK profiles of both loaded and unloaded drugs (released) are crucial to understand the PK properties of the nanomedicines and how it affects both their pharmaco-and taxico-dynamics. [112] The PK profile of the formulation can quantitatively describe how the body handles the drugs and/or nanoparticles. Important parameters for this include, C max (maximum concentration), t 1/2 (half-life), Cl (clearance), AUC (area under the curve) and, most importantly, the maximum tolerated dose (MTD).…”