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PK/PD modeling within
Is it used? Can it be used and if yes, where?
Views from industry
24 September 2008
• PK/PD modeling offers a valuable tool to assist in
some cases with establishing an effective dose and
• PK/PD modeling is mostly used in the research and
early development phases
– relationship between PK and efficacy
– may also be used in development when PK/PD
models are well established and recognized both
by the regulatory authorities and the scientific
• Interpretation is controversial and a general definition
is still missing and under considerable discussion.
• What do we need to know to determine dose, route,
– Host physiology;
• The end results should be a safe and realistic dosage
regimen – interval the clinician or owner will obey.
Remember: Rational Design of Safe
and Effective Dosage Regimen(s)
Require Knowledge and Judgment !
Condition being treated
Route of Administration
Other disease states
Multiple Drug Therapy
Convenience of Regimen
When a disease model is not available, PK/PD can only be
done on clinical cases with the limitations of variability,
number of blood samples and endpoint/efficacy
When a PK/PD modeling is possible, the model must be
chosen to reflect as far as possible the disease pattern and
severity or be recognised in the specific literature.
There may be clinical conditions where a PK/PD model will
not result in an effective method to predict clinical outcomes
(e.g. plasma concentration do not reflect PD action).
Reliable PK/PD relationship very often only are established at
the end of the development program.
• Ideally the model will be based on a complete range of
responses requiring appropriate designed studies which
may not always be practical.
• For antibiotics surrogate markers were developed in
immunocompromised animals and only for specific bug
drug combinations. In addition, the MIC is a useful but
imprecise parameter, measured in vitro.
• Simple and sometimes unrealistic assumptions are
critical in biological models.
• Hence “all models are wrong, but some are more
useful than others” and applying PK/PD alone can lead
to unncessarily high doses.
• PK/PD may replace a dose determination study saving
time, reducing costs and use of animal testing.
• PK/PD data are helpful in case of field trial license
applications and in supporting line extensions for well
• PK/PD can be used to simulate efficacy/safety
outcomes in different routes and doses, to minimise
additional animal experiments.
What sort of training is required for PK/PD
• PK/PD modeling should be performed by scientists with
a strong background in pharmacometrics: statistics,
pharmacokinetics and a firm understanding of the
mechanisms of PD models.
• While human PK/PD training will allow for
understanding of PK/PD models, an understanding of
comparative physiology (veterinary pharmacology) is
essential to interpreting the results and limitations of
For regulatory submissions, PK/PD modeling should be
accepted when available but must not be systematically
PK/PD should not be a tool to assess the efficacy of well
established products that have demonstrated efficacy under
normal conditions of use and for which there are no
pharmacovigilance alerts or changing resistance rates.
When feasible, PK/PD data should be considered a
substitution, but not an additional requirement.
– The conditions under which PK/PD modeling can substitute
other methods should be clarified.
PK/PD reports should be signed by authors with strong
knowledge and background on comparative physiology statistics,
pharmacokinetics, pharmacology, toxicology, clinical models, etc.