TABLE 2

Comparison of acetaminophen PBPK model predicted and observed PK data

Clinical studies were used as the training and validation sets. The observed and the predicted C_max (µg/ml) and AUC (µg⋅h/ml) (mean, lower and higher 95% CI of the proteomics data of DMEs) for these studies are shown for all pediatric and adult populations and for the intravenous and oral routes of administration. The simulated mean C_max (µg/ml) and AUC (µg⋅/ml) values were compared with the observed data and the acceptance criteria [on the basis of bioequivalence criterion (1.25-fold), 2-fold criterion, and population-based criterion] was determined. Study ID in the table represent the following: 1 (Clements et al., 1984); 2 (Singla et al., 2012); 3 (Rawlins et al., 1977); 4 (Perucca and Richens, 1979); 5 (Prescott, 1980); 6 (Zapater et al., 2004); 7 (Rostami-Hodjegan et al., 2002); 8 (Manyike et al., 2000); 9 (Kamali et al., 1992); 10 (Prescott, 1980); 11 (https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022450Orig1s000ClinPharmR.pdf), and 12 (Rømsing et al., 2001).

	Study ID	Dose	Parameters	Mean Observed Value (O)	Acceptance Range	Mean Predicted Value (P)	P/O Ratio	Compliance to Model Evaluation Criteria
	Study ID	Dose	Parameters	Mean Observed Value (O)	Acceptance Range	Mean Predicted Value (P)	P/O Ratio	Bioequivalence criterion	2-Fold criterion	Population criterion
Intravenous (adults)	1	5 mg/kg	AUC (0–inf, h)	18.38	15.50–21.80	18.42	1.00	Yes	Yes	Yes
	1	20 mg/kg	AUC (0–inf, h)	82.48	77.85–87.38	74.83	0.91	Yes	Yes	Yes
	2	1000 mg	C_max	21.6	15.86–29.42	30.01	1.39	No	Yes	No
	2	1000 mg	AUC (0–inf, h)	42.5	31.96–56.52	42.22	0.99	Yes	Yes	Yes
	3	1000 mg	AUC (0–inf, h)	50.5	31.50–80.96	53.42	1.06	Yes	Yes	Yes
	4	1000 mg	C_max	55.3	47.78–64.00	44.99	0.81	No	Yes	No
	5	12 mg/kg	AUC (0–inf, h)	36.7	34.23–39.35	44.76	1.22	No	Yes	No
Oral tablet (adults)	2	1000 mg	C_max	12.3	6.14–24.63	11.15	0.91	Yes	Yes	Yes
	2	1000 mg	AUC (0–6 h)	29.4	13.32–64.89	35.80	1.22	Yes	Yes	Yes
	3	500 mg	AUC (0–inf, h)	15.6	6.53–37.27	22.93	1.47	No	Yes	Yes
	3	1000 mg	AUC (0–inf, h)	44	30.87–62.72	46.40	1.05	Yes	Yes	Yes
	3	2000 mg	AUC (0–inf, h)	87.6	48.32–158.81	94.54	1.08	Yes	Yes	Yes
	6	1000 mg	C_max	15.9	11.20–22.57	11.15	0.70	No	Yes	No
	6	1000 mg	AUC (0–6 h)	38.8	32.48–46.35	35.80	0.92	Yes	Yes	Yes
	7	1000 mg	C_max	18	11.86–27.33	11.15	0.62	No	Yes	No
	7	1000 mg	AUC (0–inf, h)	54.78	45.35–66.17	46.40	0.85	Yes	Yes	Yes
	8	500 mg	C_max	5.65	3.38–9.46	5.54	0.98	Yes	Yes	Yes
	8	500 mg	C_max	4.7	3.64–6.06	5.54	1.18	Yes	Yes	Yes
Oral tablet (adults)-fed state	7	1000 mg	C_max	11	8.87–13.65	7.47	0.68	No	Yes	No
	7	1000 mg	AUC (0–inf, h)	51.92	43.51–61.95	46.44	0.89	Yes	Yes	Yes
Oral solution (adults)	9	1000 mg	C_max	17.5	9.22–33.23	13.70	0.78	Yes	Yes	Yes
	10	1000 mg	C_max	20	11.62–34.42	13.70	0.69	No	Yes	Yes
	10	1000 mg	AUC (0–24 h)	45	32.53–62.25	46.37	1.03	Yes	Yes	Yes
	4	1000 mg	AUC (0–inf, h)	49.4	42.31–57.68	46.51	0.94	Yes	Yes	Yes
	5	12 mg/kg	AUC (0–inf, h)	28	18.09–43.33	38.93	1.39	No	Yes	Yes
Intravenous (neonates)	11	15 mg/kg	C_max	25	8.88–70.35	24.75	0.99	Yes	Yes	Yes
	11	15 mg/kg	AUC (0–6 h)	62	52.91–72.65	68.66	1.11	Yes	Yes	Yes
Intravenous (infants)	11	15 mg/kg	C_max	29	10.64–79.07	27.78	0.96	Yes	Yes	Yes
	11	15 mg/kg	AUC (0–6 h)	57	40.93–79.38	53.51	0.94	Yes	Yes	Yes
Intravenous (children)	11	15 mg/kg	C_max	29	23.32–36.07	28.31	0.98	Yes	Yes	Yes
	11	15 mg/kg	AUC (0–6 h)	38	32.80–44.02	47.33	1.25	Yes	Yes	No
Intravenous (adolescents)	11	15 mg/kg	C_max	31	25.43–37.79	28.60	0.92	Yes	Yes	Yes
	11	15 mg/kg	AUC (0–6 h)	41	33.81–49.71	52.83	1.29	No	Yes	No
Oral tablet (middle childhood)	12	22.5 mg/kg	C_max	12.7	8.56–18.84	19.75	1.55	No	Yes	No
	12	22.5 mg/kg	AUC (0–4 h)	33.13	22.14–49.58	52.02	1.57	No	Yes	No