GUEST BLOGGER - JOHN REX
Dr. Rex is VP and
Global Head of Infection Development at AstraZeneca Pharmaceuticals; a
Non-Executive Director at F2G, Limited; and an Adjunct Professor of Medicine at
the University of Texas Medical School-Houston.
PK-PD underpins both our development programs and interpretive breakpoints
On 17 Oct 2013, the
FDA’s Anti-Infective Drugs Advisory Committee (AIDAC) met to discuss thechallenge of setting and updating interpretive breakpoints. For those new to the
area, interpretive breakpoints are the rules used to provide predictive
categories of Susceptible, Intermediate, or Resistant (S, I, and R) that give
health care providers a quick guide to possible antibiotic choices.
On the surface, this
sounds simple – does the drug inhibit the bacteria or not? But, the problem
becomes complex very quickly. First, the idea of “the drug” has to be
translated into “the concentration of the drug at the relevant body site when
the patient is given a specific dosage regimen.” Second, the drug’s
concentration in patients rises and falls with dosing whereas testing in the
laboratory can only for practical purposes be done at fixed drug concentrations.
Third, experience has shown that infections differ in terms of the intensity of
drug effect needed. Finally, not at all body sites are the same in terms of
drug penetration!
Despite this
complexity it has been possible to develop breakpoints for most bug-drug
combinations that offer a good aid to drug selection. But, the challenge that
has emerged is that new information has emerged over the past 20 years that has
shown us ways in which some of our breakpoints are suboptimal. Much of this
insight flows from the science of PK-PD (pharmacokinetics and
pharmacodynamics). We now have a clear understanding of how the shape of the
drug exposure curve relates to effect of the bug and how to use preclinical in
vitro and in vivo models to predict the required shape for clinical effect in
man. We also have an understanding of ways to model the shape of the curve that
deal with the fact that different individuals will have slightly different
curves – we all clear drugs from our body at a different rate and have
different volumes of distribution.
In addition, new
insights into best ways to do the in vitro susceptibility test and the
evolution of new mechanisms of resistance may have an impact on our view of the
most appropriate breakpoint. Finally, some drugs have a sufficiently broad
range of indicated dosages that a single set of breakpoints doesn’t seem
appropriate, especially give rising rates of resistance and our limited new
drug pipeline.
And finally, there was a critical need to
address this because of a problem that has come out of the woodwork as we’ve begun to implement the
streamlined development programs outlined by the 7 Nov 2013 release of the
final version of the EMA addendum on antibacterial development and the July
2013 release of the FDA’s Unmet Need guidance.
These new approaches
to development can collectively be described under the rubric of the tiered
development approach that my colleagues and I recently described in our paper
in The Lancet Infectious Diseases and will in most cases result in initial
registration based on much more focused datasets than in the past.
But (and here’s the
problem), small datasets almost invariably mean that isolates with the highest
MIC in a drug’s treatable range will NOT be seen in the course of at least the
initial development program. To understand this, see the figure at right showing
the typical frequency distribution of MICs for wild-type (non-resistant)
isolates of a any given organism vs. any given drug. Although the midpoint of
the distribution may differ across various bug-drug combinations, the 4- or
5-log2 distribution of MICs is essentially universally seen and
isolates with the highest MIC are uncommon.
Modern development
programs will always focus on providing enough drug to treat even the highest
MIC isolates. However, breakpoint setting has in the past required capture of
at least one case of patient infected with the highest MIC isolate. Absent such
experience, there has been a tendency to set breakpoints such the higher MIC
isolates are categorized as either Resistant (R) or even more confusingly as
Non-Susceptible (NS).
Whether labeled as R
or NS, the practical consequence is that the drug’s use for these isolates will
be effectively curtailed in practice. This is effectively an illogical Catch-22
— if we believe in PK-PD
for support of our trial programs and registration, we should also trust it to
help us set breakpoints.
In recognition of
all of these challenges, the
FDA convened this AIDAC and asked the committee to comment on two hypothetical
cases constructed by the FDA to represent elements of this problem.
The outcome? Although the actual votes suggest a split
views, it is important (as with all ACs) to listen not to the votes but rather
to the logic behind them. Despite a range of Yes and No votes, there was actually
near complete agreement that PK-PD really should be used to augment our
approach to setting breakpoints. Presentations from multiple societies were
supportive and the discussion by Advisory Committee really focused on the
details of how this should be done rather than on whether it
should be done.
A lot of the debate
focused on the question of how finely we could adjust the guidance. Is it, for
example, possible to have breakpoints that depend not just on the bug and drug,
but also the site of infection? The committee on the whole felt this was too
complicated to manage, especially as the laboratory can’t always infer the site
of infection from the its knowledge of specimen (e.g., an organism found in the
blood could relate to many different actual sites of infection). But, the AC
did support the idea that PK (especially PK from patients) could be the basis
for recommending dosage adjustments that would permit a single set of
breakpoints to be applied across all indications.
All of this is, in my
view, a really encouraging demonstration of how we are using science-based
logic to enable the development of much-needed and potentially life-saving
antibiotics prior to future epidemics of highly resistant bacteria.
John H. Rex, MD
No comments:
Post a Comment