Experience In Using PBPK Models in Clinical Pharmacology Reviews
Experience In Using PBPK Models in Clinical Pharmacology Reviews
Experience In Using PBPK Models in Clinical Pharmacology Reviews
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<strong>PBPK</strong> Provides <strong>In</strong>sights of Mechanism and Time-variation<br />
Mean hepatic CL'<strong>in</strong>t_CYP3A4 (L/hr)<br />
QD400 achieved maximal<br />
<strong>in</strong>hibition but returned<br />
close to basel<strong>in</strong>e before<br />
the next dose<br />
Mean <strong>in</strong>test<strong>in</strong>al CL'<strong>in</strong>t_CYP3A4 (L/hr)<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
0.7<br />
0.6<br />
0.5<br />
0.4<br />
0.3<br />
0.2<br />
0.1<br />
0<br />
Mean Liver CL’ <strong>in</strong>t,CYP3A=76 L/hr<br />
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 360<br />
Time (hr)<br />
Mean <strong>In</strong>test<strong>in</strong>e CL’ <strong>in</strong>t,CYP3A=0.64 L/hr<br />
No KTZ_Hepatic<br />
KTZ 400 mg QD<br />
KTZ 200 mg BID<br />
60% Basel<strong>in</strong>e_Hepatic<br />
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 360<br />
Time (hr)<br />
No KTZ_<strong>In</strong>test<strong>in</strong>al<br />
KTZ 400 mg QD<br />
KTZ 200 mg BID<br />
60% Basel<strong>in</strong>e_<strong>In</strong>test<strong>in</strong>al<br />
BID200 generally<br />
ma<strong>in</strong>ta<strong>in</strong>ed >40%<br />
<strong>in</strong>hibition<br />
Zhao et al, J Cl<strong>in</strong> Pharmacol, 2009<br />
� Should ketoconazole be adm<strong>in</strong>istered 400 mg QD or 200 mg BID?<br />
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