Drug Metabolism in Drug Design and Development Basic Concepts and Practice

another study, 20 or 40 mg conivaptan was given orally twice a day from Day 2
to Day 6 and simvastatin 60 mg was given orally on Day 1 and Day 6. The
pharmacokinetic parameters of simvastatin and simvastatin acid were
increased to a much greater extent (Table 7.10). It is worth noting that the
treatment of oral conivaptan 20 and 40 mg bid for 5 days only increase oral
midazolam (2 mg) AUC by 3.5- and 5.8- fold, respectively.
Because demonstrated above, oral administration will carry a high risk for
severe adverse drug interactions. Conivaptan was eventually reformulated for
intravenous administration late in the drug development program, which
greatly reduced the risk for adverse drug interactions, especially for marketed
CYP3A4 sensitive substrate drugs and strong inhibitory drugs. The intrave-
nous administration of conivaptan makes the risk management program much
easier to limit the drug to hospitalized patients only. The regulatory agency
concluded that the drug can be administered effectively and safely if limited to
the intravenous route.

7.5 Conclusions

Regulatory agencies have been advocating a science-based review process, have
been closely monitoring the emergence of new science and have been updating
their regulatory guidances in a timely manner, especially in the field of drug
metabolism and drug interactions. The FDA 2006 draft guidance for ‘‘Drug
Interaction Studies––Study Design, Data Analysis, and Implications for
Dosing and Labeling’’ has collected a consensus among scientists from
regulatory, pharmaceutical industry, and academic fields. Its contents and
scope are substantial and sophisticated. When the new draft guidance is
finalized, it will eventually replace the 1997in vitrometabolism and the 1999
in vivometabolism/drug interaction guidances. The 2006 draft guidance for
drug interactions has incorporated many new developments and can be used as
an excellent reference tool for all scientists in the field. The new guidance on
drug interactions also will increase acceptance for including study results in the
drug product labeling using preferred substrates, inhibitors, and study design
fromin vitroandin vivodrug metabolism and drug interaction studies.
The FDA draft guidance ‘‘Safety Testing of Drug Metabolites,’’ together
with the MIST document, has opened a new chapter of drug metabolism

TABLE 7.10 Effect of oral conivaptan bid on simvastatin and simvastatin acid:
mean ratio of Day 1 versus Day 6.

Parameter

Conivaptan 20 mg q12 h 6 days Conivaptan 40 mg q12 h 6days

Simvastatin Simvastatin acid Simvastatin Simvastatin acid

Cmax 7.9 14.4 3.12 18.1
AUC (0– 1 ) 6.0 13.0 4.22 19.8

CONCLUSIONS 231