Sequential application of topical medications – applying two or more agents to the same anatomical site – is common in dermatologic practice, particularly for chronic inflammatory conditions requiring combination therapy. Despite its routine use, guidance on application order, timing, and vehicle compatibility remains limited, and the pharmacologic consequences of sequential topical application are not well defined. This review synthesizes current clinical, in vivo volunteer, and mechanistic in vitro/ex vivo evidence evaluating how sequential application influences percutaneous absorption, cutaneous bioavailability, and clinical outcomes. A qualitative literature search identified twelve eligible studies, including randomized controlled trials, in vivo human studies, and mechanistic diffusion and visualization models. Across heterogeneous designs, sequencing was not pharmacologically neutral. Observed effects were driven primarily by barrier state and vehicle/excipient interactions rather than formulation labels alone. Sequencing was most consequential when the first-applied product altered the stratum corneum through keratolysis, hydration or occlusion, or lipid film formation, or when vehicle interactions resulted in redissolution or redistribution of previously applied agents. In barrier-deficient conditions, such as atopic dermatitis, the order of application had less impact on clinical outcomes. Fixed-combination products generally demonstrated more consistent and predictable delivery than free sequential regimens. Collectively, the available evidence supports a mechanism-informed approach to topical sequencing and highlights the need for standardized, clinically relevant studies to guide application order and timing as combination topical therapy continues to expand.
Burstein et al. (Thu,) studied this question.