Application of Virtual Twin PBPK Models in Individuals with Obesity via CYP3A4 Phenotyping Using Endogenous Biomarker Data

Physiologically-based pharmacokinetic (PBPK) models personalized via virtual twins using endogenous biomarker 4β-OHC for continuous *CYP3A4* phenotyping in obese individuals

A prospective study in 54 pre- and 30 post-bariatric surgery (Roux-en-Y) patients validates the use of the endogenous biomarker 4β-hydroxycholesterol (4β-OHC/C) for continuous CYP3A4 phenotyping and individualized PBPK virtual twin construction. These models achieve 85–87% predictions within twofold of observed concentrations for CYP3A4 substrates (midazolam, atorvastatin). The approach allows dynamic dose adjustment throughout the weight-loss trajectory, without an exogenous marker.

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The use of endogenous biomarkers for continuous CYP3A4 phenotyping represents a pragmatic advance: no probe drug, no dedicated additional blood draw. Validation in the obesity context — where pharmacokinetic changes are major and variable — is particularly relevant for precision medicine in bariatric surgery.