Impact of PKRelated Variants on Later Product Development

The identification of Pgx markers predicting drug PK provides an option for dose customization strategies. Addition of subgroups for specialized dose-response analysis within the context of clinical development will add complexity and cost to drug trials. Therefore, the impact of the dose customization should be assessed with regard to clinical outcomes.

In many cases, early clinical studies, which carefully monitor PK, are insufficiently powered to identify potential genetic sources of PK variability. However, the goal to understand exposure-response relationships may lead to more extensive monitoring of PK in later trials, where subject numbers are higher. If variable exposures are associated with adverse events, the goal is to identify the sensitive patient subset by genomic or genetic screening. If variable exposures are clearly associated with responses, the underlying mechanisms could be addressed by patient selection, dose customization, or advanced molecular design to overcome the differential effect (e.g., engineering of Fc constructs to avoid effects of FcR polymorphisms or to improve half-life through the FcRn recycling pathway).

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