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