are those of interference by concomitant drugs.
One somewhat historical example is that for
some of the older, less specific antibodies, spiro-
nolactone, vitamin D and carbamazepine can all
interfere with digoxin radioimmunoassays; this
remains a problem in less wealthy countries.
20.4 Preclinical investigations
and clinical trials
to investigate interactionsDevelopment plans for new drugs should include
screening for potential drug interactions at an early
stage. Structural chemistry and other chemical
properties will give a broad idea of how the drug
may be absorbed, transported, metabolized and
excreted. Mechanistic studies to elucidate the
mechanism of action will give indications for pos-
sible interactions with other drugs acting at the
same site.In vitroandin vivoinvestigations on
hepatic enzyme systems can be carried out to
investigate the substrate potential and/or capability
for inhibition or induction of liver enzyme systems;
this information can then be used to guide investi-
gations of metabolic interactions that may be of
eventual clinical significance. The animal toxico-
kinetics may also provide information about what
can be expected in humans.
These batteries of preclinical tests will often
generate questions that can only be answered by
studying potential interactions in humans. Under-
standing whether a new drug will interact with
other drugs that are likely to be co-prescribed for
the disease of interest is essential for good product
labeling. Oral contraceptives are used by about
50% of women in their reproductive years in the
developed world, and must always be considered
as a concomitant medication.
Clinical trial design for drug
interactions
Drugs in development usually have to undergo a
number of human interaction studies before they
can be administered to patients (often on stable
co-medications), whether in phase III clinical trials
or after marketing authorization was obtained. It is
hard to generalize about the number and type of
interaction studies that are needed for new drugs
because these depend on so many aspects of the
preclinical profile and target disease (see above).
The design of individual studies that address
possible interactions through the CYP450 meta-
bolic pathway are, although often somewhat
stereotypical, never completely standard. Usually
these are phase I healthy volunteer studies which
have primary end points of a pharmacokinetic
nature. The studies can usually be done in an
open-label fashion and without the use of placebo,
because the end point is objective: drug concentra-
tions reported in the laboratory cannot be influ-
enced by investigator bias.
Prior to study design, the available data need to
be examined to understand, whether the study drug
is expected to be an inhibitor or inducer of any
important CYP450 isoenzyme, or is a substrate
competing for one of them. If there isa priori
understanding of the putative metabolic path-
way(s), then it can be possible to design a single
study which screens broadly across all those iso-
enzymes that are commonly involved in drug meta-
bolism in humans.
Enzyme competition or inhibition occurs
quickly and can often be demonstrated with a
single-dose design. Inhibition tends to be very
specific for a given isoenzyme. Offset of inhibition
can be fast or slow. Straightforward substrate com-
petition wears off as quickly as the fastest of the
interacting drugs is eliminated. However, covalent
binding of drug to the receptor or enzyme of inter-
est is irreversible. A good example is proton-pump
blockade, where recovery requires regeneration of
the proton transporter, and takes several days.
Many inhibitory effects are dose-dependent and
only reach clinically significant levels of inhibition
at greatly supra-therapeutic doses. It is, therefore,
important in first interaction studies to plan for
more than one dose level.
Enzyme induction is usually dose-dependent
and typically needs 10–14 days of repeat dosing
to develop to its full extent. Enzyme induction is
generally less specific than enzyme inhibition
and can be observed across a broad range of20.4 PRECLINICAL INVESTIGATIONS AND CLINICAL TRIALS TO INVESTIGATE INTERACTIONS 261