Drug Metabolism in Drug Design and Development Basic Concepts and Practice

(e.g., Phase II or renal excretion), then, the likelihood of a drug interaction is
reduced and even large [I]/Kiratios become irrelevant.
Use ofin vitrodata to prospectively predict DDIs is difficult and some have
proposed a relatively simple ‘‘rank-order’’ approach (Obach et al., 2005). In
this instance, a NCE is evaluated as an inhibitor of different CYP forms
in vitro. Standardized incubation conditions are employed, so that the IC 50 sor
Kis for each CYP form are ranked in order of increasing potency. The CYP
form with the lowest IC 50 orKiis evaluated first in the clinic. For example, the
inhibition is greatest with CYP3A4, and then a midazolam clinical DDI study
is initiated first. Other CYPs are followed up with suitable probe drugs as
needed (Table 5.4).

5.2.4 Clinical Evaluation of Inhibition

Treatment modalities employing combinations or cocktails of several drugs
have become more commonplace. Therefore, clinically relevant drug–drug
interactions are sometimes inevitable, and have become an important safety
and regulatory concern. The pharmaceutical industry has, therefore, responded
and it is now routine to conduct DDI studies during clinical development in
order to identify and characterize potential CYP liabilities, and to provide such
information to health care providers should a NCE become a marketed drug.
Clinical evaluation of CYP inhibition is most valuable if studies are
conducted within the context of clinical relevance. For drugs with a wide
therapeutic window, pharmacokinetic DDIs, to some degree, can be tolerated.
On the contrary, a small increase in systemic exposure may lead to detrimental

TABLE 5.4 Examples of CYP substrates and inhibitors used in clinical DDI studies.a

CYP
isoform Substrates Inhibitors Inducers

1A2 Caffeine, theophyline Fluvoxamine Smoking
2A6 Not available Not available Not available
2B6 Efavirenz Not specified Rifampin
2C8 Repaglinide, rosiglitazone Gemfibrozil Rifampin
2C9 Warfarin, tolbutamide Fluconazole (use
of PM subjects)

Rifampin

2C19 Omeprazole Omeprazole, fluvoxamine
(use of PM subjects)

Rifampin

2D6 Desipramine,
dextromethorphen

Quinidine, paroxetine

(use of PM subjects)

Not identified

2E1 Chlorzoxazone Disulfirum Ethanol
3A4/3A5 Midazolam, buspirone,
felodipine, simvastatin

Ketoconazole, itraconazole Rifampin,

carbamazepine

aAdapted from (Bjornsson, 2003; Tucker, 2001), November 1999 FDA Guidance for Industry, and
2004 Preliminary Concept paper (www.fda.gov).
PM: Poor metabolizers.

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