1. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 1 Improvement in Dose Selection: FDA Perspective IDSA/ISAP/FDA Workshop April 16, 2004 Jenny J Zheng, Ph.D. Pharmacometrician DPEIII/OCPB/CDER/FDA IDSA/ISAP/FDA Workshop April 16, 2004 Jenny J Zheng, Ph.D. Pharmacometrician DPEIII/OCPB/CDER/FDA

2. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 2 ObjectivesObjectives To discuss the studies to support dose selection To discuss a model based quantitative approach to guide dose selection To discuss approaches to further advance the use of PK/PD for dose selection To discuss the studies to support dose selection To discuss a model based quantitative approach to guide dose selection To discuss approaches to further advance the use of PK/PD for dose selection

3. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 3 Dose Selection Efficacy Safety Efficacy Safety Resistance

4. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 4 Studies to Support Dose Selection 1. Microbiology / in vitro data Susceptibility data for pathogens relevant to the indication Protein binding Post antibiotic effect (PAE) 2. Pre-clinical data PK/PD studies in various animal/in vitro models Efficacy studies in various therapeutic infection models PK studies in the animals used in therapeutic infection models 1. Microbiology / in vitro data Susceptibility data for pathogens relevant to the indication Protein binding Post antibiotic effect (PAE) 2. Pre-clinical data PK/PD studies in various animal/in vitro models Efficacy studies in various therapeutic infection models PK studies in the animals used in therapeutic infection models

5. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 5 Studies to Support the Dose Selection 3. Phase 1 pharmacokinetic studies PK studies in healthy subjects 4.Phase 2 studies Efficacy Safety 3. Phase 1 pharmacokinetic studies PK studies in healthy subjects 4.Phase 2 studies Efficacy Safety

6. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 6 Time to Communicate with FDA Early communication is encouraged. Prior to phase 2/3 studies Early communication is encouraged. Prior to phase 2/3 studies

7. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 7 How to Select Dose Rationale for dose selection in antimicrobial drug applications is variable. Very often the dose is selected based on mean PK profile in relation to MIC for relevant pathogens. –The PK variability of drug is not considered. –The relationship between a concentration- time profile and a MIC is not always clear. A quantitative approach is recommended. Rationale for dose selection in antimicrobial drug applications is variable. Very often the dose is selected based on mean PK profile in relation to MIC for relevant pathogens. –The PK variability of drug is not considered. –The relationship between a concentration- time profile and a MIC is not always clear. A quantitative approach is recommended.

8. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 8 Quantitative Approach What is quantitative approach? –Use modeling and simulation tools to quantitatively predict the outcome. Advantage of quantitative approach –Quantitative (predictive) –Decision is more logical and transparent –Objective What is quantitative approach? –Use modeling and simulation tools to quantitatively predict the outcome. Advantage of quantitative approach –Quantitative (predictive) –Decision is more logical and transparent –Objective

9. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 9 Quantitative Approach Dose X Pathogen Can pathogen be killed at dose X? A PK/PD index can be obtained from pre-clinical studies and be used to predict the bacterial killing/inhibition effect. If the PK/PD index for the unbound drug in the subject is above the PK\PD index obtained from pre- clinic: YES. Otherwise: NO PK Protein binding

10. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 10 The Goal To predict the percentage of patients who could reach a PK/PD target at a range of doses. Dose/doses can be determined for clinical trials: –Phase 3 (fixed dose): majority of subjects would reach the PK/PD target. –Phase 2 dose ranging studies: the doses should be selected so that it is differentiable with regard the percent of subjects who could reach the PK/PD target among the doses. To predict the percentage of patients who could reach a PK/PD target at a range of doses. Dose/doses can be determined for clinical trials: –Phase 3 (fixed dose): majority of subjects would reach the PK/PD target. –Phase 2 dose ranging studies: the doses should be selected so that it is differentiable with regard the percent of subjects who could reach the PK/PD target among the doses.

11. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 11 The Method PK data PK model (parameters and its variability) PK profiles at doses even not studied.

12. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 12 The Method Distribution of PK/PD index at dose X 77%

13. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 13 The Method MIC 90 =0.5  g/mL MIC 90 =1  g/mL MIC 90 =2  g/mL X1 X2 X3X4

14. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 14 Antimicrobial Model Successful treatment of infection involves the interactions of host, drug and bacteria HostDrug Bacteria s Pharmacokinetics Tissue penetration Susceptibility of pathogens PK/PD relationship PAE Killing rate Other metrics Immune system ? ? ? ?    The factors not being considered may represent potential limitations.

15. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 15 PK/PD Studies in Human The predictability of PK/PD relationship in animals for treatment of infections in human is not clear. The PK/PD relationship for most of drugs was established only in animals. To improve understanding the PK/PD relationship in human: –Phase 2/3 studies The predictability of PK/PD relationship in animals for treatment of infections in human is not clear. The PK/PD relationship for most of drugs was established only in animals. To improve understanding the PK/PD relationship in human: –Phase 2/3 studies

16. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 16 SummarySummary A model based quantitative approach is informative for dose selection. With the potential limitations, the dose should be selected based on the totality of available data. Dose selection: A model based quantitative approach is informative for dose selection. With the potential limitations, the dose should be selected based on the totality of available data. Dose selection: Microbiology Pre-clinic Phase 1Phase 3Phase 2

17. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 17 FutureFuture Well designed dose ranging phase 2 studies in appropriate infections. –PK/PD relationship in human –Safety Improvement of the model used in quantitative approach. –Efficacy + Safety + Resistance Evaluation of indices other than AUC/MIC, C max /MIC, and T>MIC. Development of optimal duration of therapy. Well designed dose ranging phase 2 studies in appropriate infections. –PK/PD relationship in human –Safety Improvement of the model used in quantitative approach. –Efficacy + Safety + Resistance Evaluation of indices other than AUC/MIC, C max /MIC, and T>MIC. Development of optimal duration of therapy.