1. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 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 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. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 2 ObjectivesObjectives 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 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. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 3 Use of In Vitro/Animal Models in Drug Development Primary purpose is the delineation of the principal PK/PD indexPrimary 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 AUC 0-24 /MIC, C max /MIC, and T>MICMost common PK/PD indices consist of the AUC 0-24 /MIC, C max /MIC, and T>MIC –definition of PK/PD indices not standardized –other PK/PD indices should be considered Primary purpose is the delineation of the principal PK/PD indexPrimary 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 AUC 0-24 /MIC, C max /MIC, and T>MICMost common PK/PD indices consist of the AUC 0-24 /MIC, C max /MIC, and T>MIC –definition of PK/PD indices not standardized –other PK/PD indices should be considered

4. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 4 Use of In Vitro/Animal Models in 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 trialsConsideration 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 encouragedSubmission 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 outcomeInformation obtained from in vitro/animal models has the potential to increase the probability of a successful clinical outcome Consideration of the principal PK/PD index and magnitude should be used to determine the dosage regimens evaluated in Phase 2/3 clinical trialsConsideration 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 encouragedSubmission 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 outcomeInformation obtained from in vitro/animal models has the potential to increase the probability of a successful clinical outcome

5. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 5 Considerations for Using In Vitro/ Animal Models in Drug Development Protein bindingProtein binding –protein binding not always taken into consideration –commonly reported as total concentrations Initial inoculaInitial inocula –may reveal different outcomes from similar exposures Pre-treatment intervalPre-treatment interval –ranges from immediate to several hours –relation to established infection in humans Protein bindingProtein binding –protein binding not always taken into consideration –commonly reported as total concentrations Initial inoculaInitial inocula –may reveal different outcomes from similar exposures Pre-treatment intervalPre-treatment interval –ranges from immediate to several hours –relation to established infection in humans

6. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 6 Considerations for Using In Vitro/ Animal Models in Drug Development Duration of experimentDuration of experiment –usually 24 hours –longer experiments may reveal different outcomes Surface area to volume ratio (in vitro models)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 modelsThe half-life can be easily altered with in vitro models –may help to determine the appropriate dosing frequency Duration of experimentDuration of experiment –usually 24 hours –longer experiments may reveal different outcomes Surface area to volume ratio (in vitro models)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 modelsThe half-life can be easily altered with in vitro models –may help to determine the appropriate dosing frequency

7. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 7 Determination of the Principal PK/PD Index Usually involves a large number of doses and dosing intervals (dose fractionation)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 Usually involves a large number of doses and dosing intervals (dose fractionation)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. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 8 Determination of the Principal PK/PD Index Commonly assess ATCC strains for select Gram- positive and Gram-negative organismsCommonly 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 organismRange 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 Commonly assess ATCC strains for select Gram- positive and Gram-negative organismsCommonly 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 organismRange 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. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 9 Determination of the Principal PK/PD Index Delineation of the PK/PD index usually based on the coefficient of determination of sigmoid Emax analysisDelineation 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 agreementResults from in vitro/animal models should be in agreement Ideally, results should be confirmed from more than one pre-clinical studyIdeally, results should be confirmed from more than one pre-clinical study Delineation of the PK/PD index usually based on the coefficient of determination of sigmoid Emax analysisDelineation 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 agreementResults from in vitro/animal models should be in agreement Ideally, results should be confirmed from more than one pre-clinical studyIdeally, results should be confirmed from more than one pre-clinical study

10. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 10 Determination of the Magnitude of the Principal PK/PD Index Magnitude of principal PK/PD index is dependent upon endpointMagnitude 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 modelsImpact of immune function not always assessed in animal models –neutropenic vs. immunocompetent animals –relation to hospital-acquired vs. community-acquired infections? Magnitude of principal PK/PD index is dependent upon endpointMagnitude 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 modelsImpact of immune function not always assessed in animal models –neutropenic vs. immunocompetent animals –relation to hospital-acquired vs. community-acquired infections?

11. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 11 Determination of the Magnitude of the Principal PK/PD Index Degree of protein bindingDegree of protein binding –PK/PD calculations should clearly state whether total or unbound concentrations were utilized Degree of protein bindingDegree of protein binding –PK/PD calculations should clearly state whether total or unbound concentrations were utilized

12. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 12 Use of In Vitro/Animal Models to Determine Phase 2/3 Dosage Regimens Consideration of target populationConsideration of target population –community-acquired vs. nosocomial infections Dose ranging studies based on endpointDose 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 endpointDose ranging studies based on percentage of population achieving endpoint –e.g., 100% achieving target (highest dose), 80% achieving target (lowest dose) Consideration of target populationConsideration of target population –community-acquired vs. nosocomial infections Dose ranging studies based on endpointDose 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 endpointDose ranging studies based on percentage of population achieving endpoint –e.g., 100% achieving target (highest dose), 80% achieving target (lowest dose)

13. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 13 Considerations for Animal Therapeutic Models Animal therapeutic models have been developed for various infectionsAnimal therapeutic models have been developed for various infections –e.g., endocarditis, pneumonia, meningitis Well designed animal therapeutic models can provide important information for clinical trialsWell 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 Animal therapeutic models have been developed for various infectionsAnimal therapeutic models have been developed for various infections –e.g., endocarditis, pneumonia, meningitis Well designed animal therapeutic models can provide important information for clinical trialsWell 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. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 14 Considerations for Animal Therapeutic Models Dose ranging PK/PD studies performed in animal therapeutic models may provide additional information to support clinical efficacyDose 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 settingPotential 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 Dose ranging PK/PD studies performed in animal therapeutic models may provide additional information to support clinical efficacyDose 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 settingPotential 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. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 15 Unresolved Issues With Animal Therapeutic Models Emay depend upon various factors: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 humansDrug 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 Emay depend upon various factors: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 humansDrug 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. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 16 ConclusionsConclusions 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 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. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 17 “Closing the Loop” In-Vitro/ Animal Models Phase 1 Studies Phase 2 Studies Phase 3 Studies Pre-Clinical Clinical Development