In Vitro/Animal Models to Support Dosage Selection: FDA Perspective

1. In Vitro/Animal Models to Support Dosage Selection: FDA Perspective IDSA/ISAP/FDA Workshop April 16, 2004 Charles R. Bonapace, Pharm.D. Division of Pharmaceutical Evaluation III Office of Clinical Pharmacology and Biopharmaceutics Food and Drug Administration

2. Objectives • To discuss the role of in vitro/animal models in drug development • To discuss characteristics of in vitro/animal models that should be stated in study reports • To discuss the endpoints of in vitro/animal models in relation to Phase 2/3 clinical studies • To discuss limitations of therapeutic animal models

3. Use of In Vitro/Animal Modelsin Drug Development • Primary purpose is the delineation of the principal PK/PD index • can easily assess a wide range of doses/dosing intervals • not always obtainable from clinical trials due to dosing limitations/ethical considerations • Most common PK/PD indices consist of the AUC0-24/MIC, Cmax/MIC, and T>MIC • definition of PK/PD indices not standardized • other PK/PD indices should be considered

4. Use of In Vitro/Animal Modelsin Drug Development • Consideration of the principal PK/PD index and magnitude should be used to determine the dosage regimens evaluated in Phase 2/3 clinical trials • Submission of in vitro model data in addition to animal model data are encouraged • Information obtained from in vitro/animal models has the potential to increase the probability of a successful clinical outcome

5. Considerations for Using In Vitro/Animal Models in Drug Development • Protein binding • protein binding not always taken into consideration • commonly reported as total concentrations • Initial inocula • may reveal different outcomes from similar exposures • Pre-treatment interval • ranges from immediate to several hours • relation to established infection in humans

6. Considerations for Using In Vitro/Animal Models in Drug Development • Duration of experiment • usually 24 hours • longer experiments may reveal different outcomes • Surface area to volume ratio (in vitro models) • impacts the shape of the concentration-time profile in the peripheral compartment (2-compartment model) • The half-life can be easily altered with in vitro models • may help to determine the appropriate dosing frequency

7. Determination of the PrincipalPK/PD Index • Usually involves a large number of doses and dosing intervals (dose fractionation) • degree of fractionation is not consistent between studies • other designs that have the same rationale are acceptable • consideration should be given to the dosing frequency (e.g., q2h-q12h) with concentration-dependent drugs

8. Determination of the PrincipalPK/PD Index • Commonly assess ATCC strains for select Gram-positive and Gram-negative organisms • may not represent organisms likely to be encountered in clinical infections • single isolate used to represent a genus and species • Range of MIC values commonly not assessed for an organism • range in effect based on altering dose/dosing interval, not MIC • impact of range in MIC values on the principal PK/PD index usually not assessed

9. Determination of the PrincipalPK/PD Index • Delineation of the PK/PD index usually based on the coefficient of determination of sigmoid Emax analysis • method used to determine the principal PK/PD index not always stated • Results from in vitro/animal models should be in agreement • Ideally, results should be confirmed from more than one pre-clinical study

10. Determination of the Magnitude of the Principal PK/PD Index • Magnitude of principal PK/PD index is dependent upon endpoint • e.g., static effect, 1-log kill, 2-log kill, or Emax effect • should depend upon the endpoint that is associated with clinical outcome • Impact of immune function not always assessed in animal models • neutropenic vs. immunocompetent animals • relation to hospital-acquired vs. community-acquired infections?

11. Determination of the Magnitude of the Principal PK/PD Index • Degree of protein binding • PK/PD calculations should clearly state whether total or unbound concentrations were utilized

12. Use of In Vitro/Animal Models to Determine Phase 2/3 Dosage Regimens • Consideration of target population • community-acquired vs. nosocomial infections • Dose ranging studies based on endpoint • e.g., 2-log kill (highest dose), 1-log kill, and static effect (lowest dose) • Dose ranging studies based on percentage of population achieving endpoint • e.g., 100% achieving target (highest dose), 80% achieving target (lowest dose)

13. Considerations for Animal Therapeutic Models • Animal therapeutic models have been developed for various infections • e.g., endocarditis, pneumonia, meningitis • Well designed animal therapeutic models can provide important information for clinical trials • potential efficacy based on drug concentration at site of infection • may provide insight for dosage regimens to be evaluated in clinical trials

14. Considerations for Animal Therapeutic Models • Dose ranging PK/PD studies performed in animal therapeutic models may provide additional information to support clinical efficacy • Potential utility will depend upon applicability to clinical setting • treatment vs. prophylaxis • differences in pharmacokinetics and tissue penetration between animals and humans • outcome may be dependent upon animal species

15. Unresolved Issues With Animal Therapeutic Models • Efficacy may depend upon various factors: • virulence/growth-phase of the bacteria • initial inoculum/time to initiation of treatment • host immune response • animal pharmacokinetics/protein binding • Drug concentrations at the site of infection may differ between animals and humans • Predictability of outcome in animals (microbiologic endpoint or survival) to humans (clinical endpoint) is not always known • Toxicity of drug in relation to efficacy

16. Conclusions • In vitro/animal models can serve as the “foundation” upon which anti-infective drug development should be based • In vitro/animal models represent an important tool for delineating the principal PK/PD index • In vitro/animal models may be used to identify dosage regimens for evaluation in Phase 2/3 studies • Ideally, the results from clinical studies should be used to confirm the in vitro/animal model endpoint associated with efficacy

17. “Closing the Loop” In-Vitro/ Animal Models Phase 3 Studies Phase 2 Studies Phase 1 Studies Pre-Clinical Clinical Development