1. DOSE SELECTION FOR ANTI-INFECTIVE DRUGS: INDUSTRY PERSPECTIVE
Dennis M. Grasela, PharmD, PhD
Executive Director, Infectious Diseases
Department of Clinical Discovery
Bristol-Myers Squibb Pharmaceutical Research Institute
FDA/IDSA/ISAP Workshop
15-16 April 2004

2. OUTLINE Exposure-Response (PK/PD) approach to dose selection
Factors driving the use of PK/PD based drug development
Potential cost benefits
Bristol-Myers Squibb Company

3. OUTLINE Exposure-Response (PK/PD) approach to dose selection
Factors driving the use of PK/PD based drug development
Potential cost benefits
Bristol-Myers Squibb Company

4. ELEMENTS OF PK/PD-BASED APPROACH TO DOSE SELECTION
Use in vitro MIC values to determine the height of the microbiological hurdle for key pathogen(s)
Use PK/PD data from in vitro hollow-fiber and in vivo animal models of infection to define PD-linked parameter and target values for key pathogen(s)
Use PK/PD modeling in ‘proof-of-principle’ studies to examine Exposure-Response relationship
Combine PK/PD-based knowledge and Monte Carlo simulations to define dose and schedule for Phase III studies
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5. MIC DISTRIBUTION FOR S. pneumoniae
Data from the SENTRY Antimicrobial Surveillance Program
1179 isolates ( ), obtained from patients aged <7 years
MIC mg/L
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6. USE OF IN VITRO MODELS TO DEFINE PD-TARGET for S. pneumoniae10 14 17 24 34 38 45
LEV
Log CFU/mL
Fig.1. Time-kill PK-PD of gatifloxacin against S pneumoniae in a hollow fiber model of infection. The numbers at the right side of each line represent the f AUC24 :MIC ratio for each experiment. The f AUC24 :MIC ratios 34 or greater resulted in the elimination of S pneumoniae from the model, whereas lesser ratios did not. (From Lister PD. Pharmacodynamics of gatifloxacin against Streptococcus pneumoniae in an in vitro pharmacokinetic model:impact of area under the curve/MIC ratios on eradication. Antimicrob Agents Chemother 2002;46:69 –74; with permission.)
Time (hours)
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Lister D. AAC. 2002; 46: 69-74

7. USE OF IN VIVO ANIMAL MODELS TO DEFINE PD-TARGET for S. pneumoniae
Bristol-Myers Squibb Company
Mattoes HM et al. AAC. 2001; 45:

8. USE OF CLINICAL DATA TO CONFIRM PD-TARGET for S. pneumoniae
Bristol-Myers Squibb Company
Ambrose PG, et al. AAC. 2001; 45:

9. Probability of Achieving Target AUC:MIC Ratio for S. pneumoniae
0.05
0.045
0.04
0.035
0.03
0.025
0.02
0.015
0.01
0.005
94% 50
100
150
200
250
300
350
400
free AUC:MIC
Ambrose PM, Grasela DM.
Diagn Microbiol & Infect Dis. 2000; 38:
Ambrose PG, Grasela D. ICAAC 1999
Bristol-Myers Squibb Company

10. OUTLINE Exposure-Response (PK/PD) approach to dose selection
Factors driving the use of PK/PD based drug development
Potential cost benefits
Bristol-Myers Squibb Company

11. DRIVERS FOR THE USE OF PK/PD Internal Factors
Knowledge-based decision making
Dose selection/confirmation
Examination of the effect of administering a dose not studied during development
Selection of target indication(s)
Enhanced understanding of the drug
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12. DRIVERS FOR THE USE OF PK/PD Internal Factors
Use of population-based PK/PD analyses
Can help explain differences in response among individuals receiving the same dose (e.g., covariate analyses)
Can help identify at risk sub-populations and define risk-benefit ratios and/or risk management strategies
Can help guide the use of pharmacogenomics
Bristol-Myers Squibb Company

13. DRIVERS FOR THE USE OF PK/PD External Factors
FDA Expectations/Opportunities
Guidances (
Population PK guidance (1999)
Exposure-Response guidance (5April 2003)
FDA Modernization Act of 1997 (FDAMA)
Global Expectations
Data-driven responses to regulatory questions and/or ‘What if scenarios’
Benefit-Risk assessment
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14. DRIVERS FOR THE USE OF PK/PD External Factors
FDA Modernization Act of 1997 (FDAMA)
Section 111 of FDAMA provides for:
“use of PK bridging studies in Pediatric studies of new drugs”
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15. DRIVERS FOR THE USE OF PK/PD External Factors
FDA Modernization Act of 1997 (FDAMA)
Section 115 of FDAMA provides for:
“new drug approval based upon evidence from a single adequate and well controlled trial, supported by confirmatory scientific evidence from other studies (e.g., Phase II PK/PD studies) in the NDA”
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16. OUTLINE Exposure-Response (PK-PD) approach to dose selection
Factors driving the use of PK-PD based drug development
Potential cost benefits
Bristol-Myers Squibb Company

17. COST BENEFITS
Population PK can obviate the need for selected clinical trials (e.g., age-gender, renal impairment, etc..)
Position sponsor to utilize provisions in the ICH E5 guidelines for the use of PK bridging studies for submission in Japan, etc…
Position sponsor to utilize provisions in Sections 111 and 115 of FDAMA
Bristol-Myers Squibb Company

18. COST BENEFITS
Selection of indications, based on PK/PD evaluation of antimicrobial spectrum
Smaller sample sizes associated with exposure-response vs. dose-response approaches
Selection of optimal dose may lower sample size requirements for non-inferiority trials
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19. Sample Size Saving with Selection of Optimal Dose in Non-inferiority Trials
Assume 90% power, with a delta of 10%, and all subjects enrolled are fully evaluable
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20. COST BENEFITS Higher quality submissions which could:
facilitate regulatory review
enhance relationship with regulatory authorities
minimize post-submission questions
Facilitate transition to novel dosage forms based on PK studies only, if PK/PD relationship is known
Provide basis for data-driven market differentiation
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21. SUMMARY
Selecting the optimal dose(s) for the treatment of infection(s) is important in order to:
Maximize efficacy
Minimize toxicity
Minimize resistance development
Using an exposure-response approach to dose selection and drug development can:
Facilitate knowledge-based decision making
Optimize trial designs
Streamline development and related costs
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