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Early prediction of elimination pathways for new chemical entities can have a profound impact on drug discovery programs. The recently proposed Extended Clearance Classification System (ECCS) is a step in the right direction, providing a framework to help identify the major elimination pathway of a drug. A list of 42 Amgen small molecules was evaluated against the ECCS framework to assess its performance in retrospectively predicting their major elimination pathway. Here, we present a critical analysis of the chemical space defined by the