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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 1 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. 2 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. 3 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 4 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. 5 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. 6 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. 7 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. 8 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. 9