Bottom‐up |
Physiochemical properties and blood binding (LogP, pKa, fup, B/P) |
Projection of human drug distribution |
Provide mechanistic understanding |
In vitro permeability and pharmaceutics information |
Projection of human PK parameters and FIH dose |
In vitro metabolism and transporters substrate data |
Enzyme/transporter DDI projection (victim and perpetrator) |
In vitro metabolism and transporters perpetrator data |
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In vivo ADME information in preclinical species |
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Top‐down |
Clinical concentration‐time profiles from single or multiple ascending doses with summary of PK parameters |
Development of model and identify parameters and their intersubject variability as well as identifying covariates |
Support clinical trial decisions |
Middle‐out |
Physiochemical properties and in vitro ADME data may be available, but key in vitro quantitative or mechanistic data may be lacking |
Refined predictions of DDI (perpetrator or victim) |
Provide mechanistic understanding and support clinical trial decisions |
Clinical concentration‐time profiles after single and multiple ascending doses with summary of PK parameters |
Special populations (pediatrics, organ impairment), |
May have clinical DDI data available as a victim and/or perpetrator for key CL pathway(s) |
Formulation optimization or selection; in silico bioequivalence |
In vivo human ADME or mass‐balance data |
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