Biomedical Engineering Reference
In-Depth Information
mechanisms of action involving alterations in the metabolic profile
of the cell. Additionally, the full magnitude of the reduction may
not become apparent for several days or more until steady state
concentrations are achieved. Alternatively, tachyphylaxis may rap-
idly occur.
To address these possibilities a common design is to conduct a
multiday study [
145
]. With this approach a full IOP “curve” is usually
collected at one or more intervals during the predose phase, onDay 1,
andon the last day of the dosingphase. IOP is usuallymeasured two to
four times per day on the intervening days. Statistically the treated
eyes may be compared to the contralateral eye (as a concurrent con-
trol), to predose values (to verify adequate acclimation), or to a
separate control group if the possibility of a contralateral effect on
IOP exists. A variety of study designs have been used to make com-
parisons between multiple concentrations, formulations, or related
compounds. Although some studies sequentially expose the set of
animals to various concentrations, formulations, or congeners there is
the risk that previous exposure may either heighten or impair
subsequent responsiveness [
146
]. Because of this, the ideal approach
would be to randomly assign individuals to various control or treat-
ment groups and evaluate all permutations simultaneously, but the
logistics of making numerous simultaneous comparisons are daunting
and the risk for a mis-dose is high.
Recovery Phase or “Wash-Out” Period
. Because of the expense asso-
ciated with acquiring and acclimating animals to IOP measure-
ments and determining their responsiveness to the class of test
article, it is often desirable to re-use the same animals to compare
different concentrations, formulations, or related compounds. The
time for the drug to “wash-out” from the animal's system varies
considerably, ranging from only a few hours to several weeks or
more. The pharmacokinetics of the test article and the duration of
therapy play important roles in determining the duration of the
washout period. Prostaglandins and rho-kinase inhibitors, which
alter complex metabolic pathways such as the extracellular matrix or
cytoskeletal elements, often require a washout period of 2-6 weeks,
whereas a week or two may be adequate for the beta-blockers
[
147
-
149
]. Usually, but not always, return to baseline IOP is a
good indicator that the drug has “washed-out”. During the recov-
ery phase delayed effects of exposure to the drug may also be
evaluated.
Although the design of toxicity studies is covered elsewhere in this
text, there are a few unique considerations in the design of anti-
glaucoma drug toxicity studies. It is important to resist the tempta-
tion to collect IOP lowering efficacy data in toxicity studies because
of the large number of confounding variables that are introduced
with a toxicity study design and because supra-therapeutic drug
5.10 A Note on
Design of Toxicity
Studies for Anti-
glaucoma Drugs
