Abstracts from the 10^th European Regional ISSX Meeting

Figures & data

Figure 1  Prediction of weight related MDZ systemic CL by incorporating either hyperbolic (A) or biphasic (B) CYP3A4 ontogeny patterns into the overall PBPK model. Solid squares plus error bars are in vivo data, grey symbols are PBPK models predictions, solid line is median prediction and dashed line 5^th and 95^th percentile.

Table 1  Predicted vs. observed PK parameters

Formulation	Tmax (h)		Cmax (mg/L)		AUC (mg/L^xh)
	Observed	Predicted	Observed	Predicted	Observed	Predicted
Slow	4.86	3.57	0.07	0.07	0.72	0.81
Moderate	3.57	3.46	0.09	0.08	0.81	0.96
Fast	3.14	3.24	0.12	0.11	0.82	1.17

Table 2  Predicted vs. observed PK parameter ratios for different formulations

Formulations Ratio	Cmax (mg/L)		AUC (mg/L^xh)
	Observed	Predicted	Observed	Predicted
Fast/Moderate	1.32	1.31	1.01	1.22
Fast/Slow	1.71	1.59	1.14	1.45
Moderate/Slow	1.30	1.19	1.13	1.19

Figure 1  Comparison of fold increases in exposure -: cirrhosis vs healthy controls (mean ± SD).

Table 1  The effect of test compounds on the accumulation (hepatocytes), BEI and Cl_biliary of d₈-taurocholate as a percentage of control (no inhibitor)

Compound	Accumulation	BEI	Clbiliary
cyclosporine 5 μM	253 ± 27.6	58.8 ± 4.07	35.6 ± 5.22
50 μM	202 ± 15.2	34.0 ± 4.69	11.4 ± 2.97
erythromycin- 5 μM	62.7 ± 12.1	88.6 ± 8.70	31.4 ± 12.4
estolate 50 μM	29.1 ± 9.42	62.9 ± 3.72	4.69 ± 1.27
glyburide 5 μM	78.7 ± 16.6	101 ± 1.32	84.2 ± 19.3
50 μM	271 ± 32.8	20.8 ± 14.2	7.72 ± 5.13
nefazodone 5 μM	85.1 ± 8.28	99.0 ± 1.19	78.6 ± 15.6
50 μM	121 ± 30.3	76.7 ± 5.62	32.9 ± 2.81
troglitazone 1 μM	76.3 ± 10.7	101 ± 2.18	80.3 ± 8.64
10 μM	32.9 ± 9.31	76.4 ± 13.1	9.23 ± 3.14

Table

Cell line	Nucleotide position in MDR1
	1236	2677	3435
MDCK-MDR1	C1236	G2677 (Ala893)	C3435
Caco-2	C1236 & T1236	G2677 (Ala893) & T2677 (Ser893)	C3435 & T3435