1. 1 PK/PD modeling within regulatory submissions Is it used? Can it be used and if yes, where? Views from industry 24 September 2008

2. 2 Introduction toolassistPK/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.

3. 3 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.

4. 4 Remember: Rational Design of Safe and Effective Dosage Regimen(s) Require Knowledge and Judgment ! Dosage Regimen Activity-Toxicity Therapeutic Window Side Effects Toxicity Concentration-Response Pharmacokinetics Absorption Distribution Metabolism Excretion Clinical Factors Weight Condition being treated Other disease states Multiple Drug Therapy Convenience of Regimen Other Factors Route of Administration Dosage Form Breed Cost ELDU Resistance

5. 5 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.

6. 6 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.

7. 7 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.

8. 8 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.

9. 9 CONCLUSIONS PK/PD modeling should be accepted when available but must not be systematically requestedFor 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. a substitution, but not an additional requirement.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.