5.4.3 Clinical Evaluation
The cost of clinical investigations, safety and regulatory concerns would likely
prohibit the development of any NCEs at high risk for significant drug–drug
interactions. In this regard, the determination of each CYP’s contribution to
overall clearance is highly desirable or required in some therapeutic areas.
Therefore, the most important utility ofin vitroCYP reaction phenotype data is
the ability to prioritize drug–drug interaction studies. This is illustrated in
Fig. 5.4 by analogy with the rank order approach described for inhibitors of
CYP (Obach et al., 2005). For instance, a ketoconazole or rifampicin
interaction study would be required if a NCE is primarily metabolized
(fm,P450>0.5) by CYP3A4. Likewise, the pharmacokinetics of a NCE would
have to be evaluated in specific populations if the compound were largely
metabolized by polymorphic CYPs, such as CYP2D6, CYP2C9, or CYP2C19.
Prospectively, there are always instances wherein vivohuman outcomes could
not be fully appreciated fromin vitrodata. Retrospectively, however,in vitro
systems are valuable tools to understand clinical drug–drug interactions.
Cerivastatin, a potent HMG–CoA reductase inhibitor, was thought to have a
low propensity for CYP-mediated drug–drug interactions because the com-
pound was metabolized by both CYP3A4 and CYP2C8; and the lack of clinically
relevant interactions with commonly used drugs appeared to support this
hypothesis (Muck, 2000). However, a significant interaction with gemfibrozil,
and concerns over severe rhabdomyolysis associated with this type of interaction,
led to its eventual withdrawal from the market (Backman et al., 2002; Roca et al.,
2002). Subsequent investigative studies indicated that gemfibrozil-O-glucuro-
nide, a major metabolite of gemfibrozil, is an inhibitor of cerivastatin hepatic
uptake transport via the organic anion transporter protein, as well as a
FIGURE 5.4 Proposed clinical drug interaction studies based onin vitroCYP reaction
phenotyping data. It is assumed that the drug in question is cleared via CYP-dependent
metabolism (fm1.0).
REACTION PHENOTYPING 129