Cutaneous Pharmacokinetic Approaches to Compare Bioavailability and/or Bioequivalence for Topical Drug Products

The practical assessment of BE for each drug product is not a one-dimensional issue, but rather, it routinely involves characterizing a multidimensional topography of product attributes and behavior that together define product performance in each case. As understanding of the physiochemical and structural complexity of semisolid drug products has evolved, it has become increasingly clear that the components, composition, and arrangement of matter in topical dermatologic products can be critical to their clinical performance.67,68 Thus, it is important to consider such molecular and macromolecular qualities in the design of bioequivalent drug products,characterizing them as rigorously as possible. This might include matching characteristics like texture, rheology, specific gravity, phase state(s), particle size and distribution of the drug substance(s), globule size and distribution, polymorphic forms, pH, and other potentially critical physicochemical and structural characteristics, as relevant to a product. It may not always be possible to identify and perfectly match the arrangement of matter between a test and reference topical dermatologic drug product (or even between manufacturing batches of a test or reference product), and so appropriate in vitro and/or in vivo tests of product performance serve an important role as part of a multicomponent risk based assessment of BE. As discussed in this work, it is now feasible for evidence from in vitro and/or in vivo cutaneous PK approaches to support a demonstration of BE. A single approach alone may not always be sufficient to demonstrate BE, but the collective weight of evidence from orthogonal methods can be highly effective in affirming BE.The rational selection of such test methods, used in combination with rigorous physicochemical and structural characterization of the drug product, is particularly valuable for the evaluation of multidimensional aspects of product quality and performance that can collectively support a demonstration of BE. Such approaches, and in particular, cutaneous PK approaches to compare BA and/or BE for topical dermatologic drug products, will likely provide an efficient path forward for developers and regulators of topical semisolid generic drug products, where no viable path had previously existed, and to provide patients with access to generic topical medications whose qualities and performance have been evaluated and matched to those of the reference product more comprehensively than ever before.

Automated summary

The practical assessment of bioequivalence (BE) for each drug product involves characterizing a multidimensional topography of product attributes and behavior. The physiochemical and structural complexity of semisolid drug products should be considered in the design of bioequivalent drug products. In addition, in vitro and/or in vivo tests of product performance and evidence from orthogonal methods can be used to support a demonstration of BE.