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PK/PD modeling within
regulatory submissions
Is it used? Can it be used and if yes, where?
Views from industry
24 September 2008
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Introduction
• PK/PD modeling offers a valuable tool to assist in
some cases with establishing an effective dose and
dosing regimen.
• 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
community
• Interpretation is controversial and a general definition
is still missing and under considerable discussion.
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Treatment Regimen
• What do we need to know to determine dose, route,
and frequency?
– Host physiology;
– Pharmacokinetics;
– Pharmacodynamics.
• The end results should be a safe and realistic dosage
regimen – interval the clinician or owner will obey.
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Remember: Rational Design of Safe
and Effective Dosage Regimen(s)
Require Knowledge and Judgment !
Activity-Toxicity
Pharmacokinetics
Therapeutic Window
Absorption
Side Effects
Distribution
Toxicity
Metabolism
Concentration-Response
Excretion
Dosage
Regimen
Clinical Factors
Weight
Other Factors
Condition being treated
Route of Administration
Other disease states
Dosage Form
Multiple Drug Therapy
Breed
Convenience of Regimen
Cost
ELDU
Resistance
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Limitations
•
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
measurement.
•
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.
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Limitations (cont’)
• 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.
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Advantages
• 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
established products.
• PK/PD can be used to simulate efficacy/safety
outcomes in different routes and doses, to minimise
additional animal experiments.
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What sort of training is required for PK/PD
assessment?
• 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
these models.
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CONCLUSIONS
•
For regulatory submissions, PK/PD modeling should be
accepted when available but must not be systematically
requested.
•
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.
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