NBCD pharmacokinetics and bioanalytical methods to measure drug release

Abstract

A primary regulatory challenge for generics of non-biological complex drugs (NBCDs) (i.e., NBCD similars or nanosimilars) is evaluation of bioequivalence (i.e., pharmacokinetic equivalence). NBCD pharmacokinetics are highly dependent upon drug release kinetics and dynamic tissue distribution, with the simultaneous existence of both NBCD encapsulated (e.g., bound) and unencapsulated (e.g. free) forms of the active pharmaceutical ingredient (API). For this reason, regulators have focused on the importance of evaluation of NBCD drug release, and the pharmacokinetics of both the encapsulated and unencapsulated forms of the API, which is challenging from a bioanalytical perspective. While many separation methods are currently available to evaluate drug release from NBCD formulations and measure encapsulated/unencapsulated forms of the API, including both direct and indirect methods, the most appropriate method for any particular NBCD type ultimately depends upon a combination of existing experience, scientific intuition, and trial and error. Presently, the available separation techniques have arisen from repurposing of small molecule preparatory and protein binding methods, none of which adequately address all concerns, such as the problems of process-induced drug release and accurate determination of unbound drug. This chapter will review the existing regulatory guidance for NBCD generic bioequivalence, as well as methods to evaluate NBCD drug release and pharmacokinetics.