In Vivo Prediction of DDIs for Competitive Inhibitors

The relationship between the magnitude of DDI and increase in drug exposure in the liver follows the following expression:

fm = fraction of the drug metabolized by the inhibited enzyme [I] = in vivo inhibitor concentration

The value of [I] in this equation has great uncertainty. Theoretically, this parameter is the concentration of the inhibitor at the site of the enzyme in the liver. The unbound hepatic inlet Cmax is the most predictive concentration (Chep,iniet,u; Obach et al. 2006) and is derived in the following way (Kanamitsu et al. 2000):

Fa — fraction of unchanged inhibitor passing through the intestine Qh — hepatic blood flow (21 mL/min/kg for humans).

Table 5.8. Impact of fm on change in DDI magnitude (AUCpo,i/AUCpo) at [I]/ Ki = 1, 10, 100

Fold change in magnitude of DDI r _(AUCp0,i /AUCp0)_

Fold change in magnitude of DDI r _(AUCp0,i /AUCp0)_

0.2

1.11

1.22

1.25

0.4

1.25

1.57

1.66

0.6

1.43

2.2

2.46

0.8

1.67

3.67

4.81

1

2.00

11.0

101

For compounds metabolized by intestinal P450 isoforms (mainly CYP3A), metabolism-based DDI in the intestine is also considered.

FG — intestinal bioavailability of the substrate

Total DDI magnitude for a competitive inhibitor — A(intestine) x A(liver).

In the FDA Draft Guidance for Industry on Drug Interaction Studies (2006), the following equation is used for competitive inhibition:

Ki where fm = 1 in the above equation and suggest a conservative [I] as a mean steady-state Cmax (bound plus unbound) following administration of the highest proposed clinical dose (Table 5.9).

Table 5.9. Prediction of clinical DDIs based on the FDA draft guidance for Industry on Drug Interaction Studies (2006)

[OK-

Potential of clinical DDIs

<0.1

Remote

0.1-1

Possible

>1

Likely

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