Transcript Regional Chapter Presidents’ Meeting

Consider Incorporating Respiratory Safety
Pharmacology Measurements into Your
Next Repeat Dose Toxicology Study
September 14, 2012
Jeff Tepper, PhD, DABT
Tepper Nonclinical Consulting
[email protected]
www.TepperTox.com
Respiratory Safety Pharmacology Objectives

Primary Goal (Tier 1): Studies “to identify undesirable pharmacodynamic properties of a substance that may have relevance to human
safety” on “functions which are acutely critical for life” prior to the first
human exposure.

Secondary Goals (Tier II):
(1)
(2)
to evaluate adverse effects observed in toxicology or clinical studies
to investigate the mechanism of adverse effects
Tier II pulmonary function testing (PFT) which may require special
procedures (e.g. anesthesia) and therefore are likely to be incorporated into
stand alone studies or possibly in toxicology studies with satellite groups.
S7A Regulatory Guidance/Leeway

It is important to adopt a rational approach when selecting and
conducting safety pharmacology studies.

The specific studies that should be conducted and their design will
vary based on the individual properties and intended use.

Moreover, the use of new technologies and methodologies in
accordance with sound scientific principles is encouraged.

Some safety pharmacology endpoints can be incorporated in the
design of toxicology, kinetic, and clinical studies …
S7A Pulmonary Function Testing Guidelines
3. Respiratory System (2.7.3) ... Respiratory rate and other measures of
respiratory function (e.g., tidal volume or hemoglobin oxygen saturation)
should be evaluated.
 Respiratory rate and tidal volume recommended (minute ventilation)
 Unanesthetized and unrestrained tests preferred
 If restrained, animals should be acclimated to testing procedure
 These requirements can be met in the context of a repeat dose GLP
toxicology study
Note: Tier I measurements are relatively insensitive, including newer less
invasive techniques (telemetry and WBP), yet they are sufficient for
detecting significant pulmonary effects.
Top 9 Reasons to Consider Incorporating
PFT into Toxicology Studies
1.
2.
3.
4.
5.
6.
7.
8.
9.
Regulatory acceptance (especially with biologics) has increased
Overall, better chance of finding and understanding any effect
Telemetry allows combined cardiopulmonary assessment
Correlative PK, Histo, Hematology, Coags & Clin. Chemistry
Serial measurements – acute and cumulative effects assessed
Larger range of doses – (hazard ID and risk assessment)
Larger N is available (increased sensitivity / statistical power)
Reduction in the overall number of animals for tox program
More efficient use of time, money and test article
Cases Where Incorporation into
Toxicology Studies may be Encouraged








Low or no level of primary or secondary pharmacology concern
Target expression, activity or exposure not in lung, nerves, muscle
When Cmax at steady state are very different then acute dosing
Cumulative effects expected based on primary or secondary
pharmacology of therapeutic/chemical class
Delayed nonclinical or clinical PFT findings observed
Local route of administration (inhaled/intranasal)
Drug accumulates in lung
Immunogenicity/antigenicity expected
Conclusions

The appropriate safety pharmacology study should be based on the
unique properties of the drug.

Drugs that are of known low risk for pulmonary effects may be good
candidates for incorporation in toxicology studies.

Drugs at high risk of demonstrating pulmonary effects should probably
be studied both in stand alone and repeat dose studies.

As techniques improve, the integrative value of incorporating safety
pharmacology into toxicology studies will have multiple benefits of
improving our science and reducing the risk to clinical trial subjects.