bioequivalence study designs are also available.
Rarely, the testing of bioequivalence at steady
state in patients is needed because normal volun-
teers would face an undue hazard, and patients
cannot ethically be withdrawn from therapy (anti-
retroviral agents are one example). Chronophar-
macological effect can also be exploited, that is
using pharmacodynamic data with a frequency and
timing of end points in much the same way as that
for the blood samples described above. This can be
useful for drugs thatare not intendedto be absorbed
systemically, for example, the rate of onset and
offset of local anesthesia to a standardized experi-
mental injury.
The Clinical Trials Directive now requires the
filing of a clinical trial application for bioequiva-
lence studies in normal volunteers or patients. In
the United States, an IND is always needed if the
generic drug is without an approved innovator in
the United States, is radioactive or is a cytotoxic.
However, when single- or multiple-dose studies
in normal volunteers do not exceed the approved
clinical dose sizes and there will be retention
samples available for inspection, then there can
be exemption from the need to file an IND. An
IND is needed for a multiple-dose bioequiva-
lence study, when it is not preceded by a single-
dose study. The usual protections for human
subjects are required, and, of course, these
include an approval from the Institutional
Review Board.
Sustained release oral formulations
By definition, sustained release formulations differ
pharmaceutically and pharmacokinetically from
the innovator drug. The excipients and particle
sizes (usually larger) of the formulation are
designed to dissolve more slowly and are almost
always drugs for chronic diseases. The common
advantages are reduction in dose frequency (and
thus, hopefully, improved patient compliance; see
that chapter in this book) or reduction ofCmaxfor a
standard AUC, which can improve tolerability
when adverse events are plasma concentration
related. Regulatory approval of these formulations
usually hinges on the following factors [see
21CFR, part 320.25(f)]:Equivalence of area under the time–plasma con-
centration curve AUC to a an the prototype
‘rapid release’ drug.Steady-state plasma concentrations that do not
exceed and are usually within a narrower range
than that of the prototype.Absence of any chance of ‘dose dumping’,
because the gross weight of active drug in a
single slow-release capsule will always exceed
that of a single dose of the prototype.Consistency of performance from dose to dose.There are various formulation tactics. Active
drug granules of larger size have smaller surface
area to volume ratios and dissolve more slowly.
These granules can also be coated with different
thicknesses of polymer, and mixtures of these can
be contained within a single capsule. Osmotically
driven tablets slowly release drug through a small
aperture during the entire traverse of the small
bowel. The tablets can be compacted with layers
that have different rates of dissolution and can
also be designed to release their contents only in
relatively alkaline environments (i.e. beyond the
ampulla of Vater). It is illogical to seek sustained
release formulations for drugs with relatively
long half times of elimination (amiodarone,
frovatriptan).Oral transmucosal formulations
The best drugs for oral transmucosal administra-
tion are those that have high potency and do not
taste bad. For example, among opioids, buprenor-
phine and fentanyl are the two drugs that have
been successfully developed using this type of
formulation. The formulations and excipients
include sublingual pellets, chewable gums and
sugary solids held on a stick, somewhat like a
lollipop.5.4 SPECIFIC FORMULATIONS 55