investigational new drug should be defined during drug development and that its
interactions with other drugs should be explored as part of an adequate
assessment of its safety and effectiveness.’’ More specifically, ‘‘the primary
metabolic pathway(s), the primary site of metabolism for the drug, and the
proportion of the total clearance that each primary metabolic pathway
constitutes should be determined at an early stage. Furthermore, the enzymes
responsible for the metabolism, potential effects of their inhibition or induction,
and possible polymorphism in the metabolism should be investigated.’’ These
documents and similar drug interaction guidances issued by the Ministry of
Health, Labor and Welfare in Japan (MHLW) describe strategies, general
methodologies and points for considerations in designing and assessingin vitro
andin vivodrug interaction studies. To address specific designs of the drug
interaction studies that are not presented in these guidances, and to harmonize
the study designs and experimental approaches, the recommendations of a
workshop attended by experts from academia, industry, and regulatory bodies
were published (Tucker, 2001). Furthermore, the PhRMA published a white
paper representing their opinion on the conduct of DDI studies (Bjornsson et
al., 2003). Recently, the FDA published a new draft guidance on drug
interaction studies (Table 7.1) (FDA, 2006a). It covers bothin vitroandin vivo
drug interaction studies with a much more detailed description of study design
and data interpretation compared to the two previously published guidances
(Table 7.1). In addition, transporter-mediated drug interactions are included in
the regulatory guidance for the first time. In Section 7.4, special considerations
in drug interaction studies are discussed.
7.2.5 Analytical Method Validation and Compliance
The FDA guidance for industry ‘‘Bioanalytical Method Validation’’ (FDA,
2001a) (Table 7.1) and the ICH guidance for ‘‘Validation of Analytical
Procedures: Text and Methodology’’ (ICH, 2005) provide general recommen-
dations for validation of bioanalytical assays using LC/MS and other
analytical techniques. These assays are mainly applied to the quantitative
determination of drugs and their metabolites in biological matrices, including
blood, plasma, urine or bile, in clinical and nonclinical studies that require
pharmacokinetic evaluation. The FDA also recommends consulting the ICH
Q3A guidance ‘‘Impurities in New Drug Substances’’ (ICH, 2006) (Table 7.1)
with regard to the development of analytical methods for measuring
metabolites in selected matrices. Maintaining records and submitting
information to the FDA electronically from bioanalytical studies should
follow FDA guidance, Part 11, Electronic Records: Electronic Signatures––
Scope and Applications (FDA, 2003c) (Table 7.1). However, there are no
specific FDA or ICH requirements or regulations with respect to analytical
methods used in drug metabolism studies. However, following the spirit of
Good Laboratory Practice (GLP) or GLP-like procedures has been
recommended by representatives from the pharmaceutical industry, regulatory
REGULATORY GUIDANCES RELEVANT TO DRUG METABOLISM 209