Method Profile
A linked parent-and-five-metabolite model projects disease-related exposure, then applies a separate analgesic exposure–response relationship.
Generate hypotheses about altered acetaminophen disposition and effect timing across metabolic and cirrhosis profiles.
GastroPlus 10.1 healthy-population model transferred to predefined overweight/obesity, NAFLD/NASH and Child–Pugh cirrhosis profiles.
Fit parent disposition before connected metabolite parameters; compare published concentration profiles and 0.5–2 prediction/observation windows, then simulate a sigmoid PD mapping.
Exposure data
Published single-dose acetaminophen data before March 2025; fixed-dose combinations excluded; 4 disease-related studies, 3 parent-only and 1 also with glucuronide/sulfate.
Metabolic and PD components
Parent, glucuronide, sulfate, NAPQI, cysteine and mercapturate; chronic-pain benchmark for a 0–10 pain-relief scale, not a disease-specific PD validation dataset.
Preserve weight/dose normalization and distinguish measured exposure comparisons from unvalidated NAPQI and PD extrapolations.
Healthy-model construction followed by literature-based disease-group comparisons; no prospective MASLD trial was conducted.
Four disease-comparison studies; fatty-liver clinical datasets include adolescents aged 12–18.
Published healthy/normal-weight/non-NAFLD controls and disease concentration profiles; predicted versus observed PK metrics.
Most parent/major-metabolite metrics fall within the 2-fold window, with metabolite overprediction including 2 of 8 glucuronide partial AUCs. Disease profiles alter predicted exposure and peak-effect timing; absolute human NAPQI validation and disease-specific analgesic validation are unavailable.
A linked parent–metabolite model explores acetaminophen exposure across obesity, fatty-liver disease and cirrhosis profiles. Predicted analgesic timing varies, while reactive-metabolite and disease-specific pharmacodynamic validation remain limited.
