7.4.2.5 Outcomes The FDA 2006 draft guidance for drug interactions states
that the results of drug–drug interaction studies should be reported as 90%
confidence intervals about the geometric mean ratio of the observed
pharmacokinetic parameters with (substrate + inhibitor) and without the
interacting drug (substrate alone). Tests of statistical significance are not
appropriate, because small, consistent systemic exposure differences can be
statistically significant (P<0.05) but not clinically relevant. When the 90%
confidence intervals for systemic exposure ratios fall entirely within the
equivalence range of 80–125%, the standard practice of regulatory authorities
is to conclude that no clinically significant differences are present unless the
sponsor has alternative predefined no effect boundaries. No effect boundaries
can also be defined based on average dose and/or concentration–response
relationships, PK/PD models, and others. No effect boundaries define the
degree of difference caused by the interaction that is of no clinical consequence.
For example, a sponsor has determined that 100 mg for Drug X is the highest
recommended dose, however, has sufficient data from the Phase III clinical
trials with 200 mg dose and the safety profiles between 100 and 200 mg are very
similar. Therefore, the sponsor could define a twofold increase in the exposure
as a no effect boundary and any pharmacokinetic drug interaction is
considered to be negative if the increase in the ratio with and without an
interacting drug is less than twofold.
7.4.3 Case Study
Conivaptan (Vaprisol^1 ), a nonpeptide, dual antagonist of arginine vasopressin
(AVP) V1Aand V 2 receptors, was approved for marketing under NDA21-697
in 2005 (http://www.fda.gov/cder/foi/nda/2005/021697s000_VaprisolTOC.
htm). Conivaptan was originally developed as a tablet intended for oral
administration. Conivaptan has nonlinear pharmacokinetics following intra-
venous infusion and oral administration. CYP3A4 was identified as the sole
cytochrome P450 isozyme responsible for its metabolism. Coadministration of
oral conivaptan hydrochloride (10 mg) with ketoconazole (200 mg) resulted in
a 4- and 11-fold increase inCmaxand AUC of conivaptan, respectively. It also
is a potent inhibitor of multiple CYP enzymes fromin vitrostudies. In one drug
interaction study, 15 mg conivaptan was intravenously administered twice a
day (8 am and 8 pm) over 120 min for 3 days (Day 3 to Day 5), and 60 mg
simvastatin was given orally on Day 1 and Day 5. The pharmacokinetic
parameters of simvastatin were increased significantly (Table 7.9). However, in
TABLE 7.9 Effect of 15 mg iv conivaptan bid on simvastatin
and simvastatin acid: mean ratio of Day 1 versus Day 5.
Parameter Simvastatin Simvastatin acid
Cmax 3.12 2.87
AUC (0– 1 ) 4.22 2.64230 REGULATORY CONSIDERATIONS OF DRUG METABOLISM AND DRUG