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

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

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

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 Bristol-Myers Squibb Company

MIC DISTRIBUTION FOR S. pneumoniae Data from the SENTRY Antimicrobial Surveillance Program 1179 isolates (1998-2002), obtained from patients aged <7 years MIC90 - 0.25 mg/L Bristol-Myers Squibb Company

USE OF IN VITRO MODELS TO DEFINE PD-TARGET for S. pneumoniae 10 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) Bristol-Myers Squibb Company Lister D. AAC. 2002; 46: 69-74

USE OF IN VIVO ANIMAL MODELS TO DEFINE PD-TARGET for S. pneumoniae Bristol-Myers Squibb Company Mattoes HM et al. AAC. 2001; 45: 2092-2097

USE OF CLINICAL DATA TO CONFIRM PD-TARGET for S. pneumoniae Bristol-Myers Squibb Company Ambrose PG, et al. AAC. 2001; 45: 2793-2797

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: 151-157. Ambrose PG, Grasela D. ICAAC 1999 Bristol-Myers Squibb Company

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

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 Bristol-Myers Squibb Company

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

DRIVERS FOR THE USE OF PK/PD External Factors FDA Expectations/Opportunities Guidances (http://www.fda.gov/cder/guidance) 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 Bristol-Myers Squibb Company

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” Bristol-Myers Squibb Company

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” Bristol-Myers Squibb Company

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

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

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 Bristol-Myers Squibb Company

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 Bristol-Myers Squibb Company

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 Bristol-Myers Squibb Company

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 Bristol-Myers Squibb Company