Evaluation of the PK / PD Changes on MASLD ‐Related Population—An Example From Simultaneous Acetaminophen Parent‐Metabolite PBPK / PD Modeling

Patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) may exhibit altered pharmacokinetics (PK) and pharmacodynamics (PD) of drugs compared with healthy populations. However, no physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model has been specifically developed for MASLD. Acetaminophen (APAP), a widely used analgesic, was selected to develop a PBPK/PD model predicting PK/PD changes of APAP and its metabolites in MASLD‐related populations. Based on a comprehensive review of published APAP PK studies and examination of existing PBPK models, a simultaneous parent‐metabolite PBPK model for APAP was developed and optimized in healthy people. The model simulated the dynamics of APAP and its five major metabolites: APAP‐glucuronide (APAP‐glu), APAP‐sulfate (APAP‐sul), N‐acetyl‐p‐benzoquinone imine (NAPQI), APAP‐cysteine (APAP‐cys), and APAP‐mercapturate (APAP‐merc). The validated model was expanded to MASLD‐related populations, including overweight, obese, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and cirrhosis with different severities. Finally, a PD model was integrated to correlate APAP's PK with pain relief scores. The PBPK model reproduced published clinical PK data for APAP and its metabolites in healthy and MASLD‐related populations. At therapeutic doses, the toxic NAPQI remained at very low levels. APAP's pain relief efficacy was retained, but onset time may change in MASLD‐related populations. This PBPK/PD approach provides a strategy for projecting drug exposure in MASLD‐related populations, even without specific PK or PD data. It highlights modeling's utility for personalized medicine in MASLD patients and MASLD treatment drug development.