# Presentation: 824479

## 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

## OUTLINE

- Exposure-Response (PK/PD) approach to dose selection
- Factors driving the use of PK/PD based drug development
- Potential cost benefits

## 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

## 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

## USE OF IN VITRO MODELS TO DEFINE PD-TARGET for S. pneumoniae

**USE OF *****IN VITRO***** MODELS TO DEFINE PD-TARGET for *****S. pneumoniae***

**Time (hours)**

**Log CFU/mL**

- Lister D. AAC. 2002; 46: 69-74

**Notes:**
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.)

## USE OF IN VIVO ANIMAL MODELS TO DEFINE PD-TARGET for S. pneumoniae

- Mattoes HM et al. AAC. 2001; 45: 2092-2097

## USE OF CLINICAL DATA TO CONFIRM PD-TARGET for S. pneumoniae

- Ambrose PG, et al. AAC. 2001; 45: 2793-2797

## Probability of Achieving Target AUC:MIC Ratio for S. pneumoniae

**Probability**

**0.05**
**0.045**
**0.04**
**0.035**
**0.03**
**0.025**
**0.02**
**0.015**
**0.01**
**0.005**
**0**

**50**

**100**

**150**

**250**

**350**

**400**

***free *****AUC:MIC**

**94%**

- Ambrose PG, Grasela D. ICAAC 1999

- Bristol-Myers Squibb Company

**Ambrose PM, Grasela DM. **
**Diagn Microbiol & Infect Dis. 2000; 38: 151-157.**

## OUTLINE

- Exposure-Response (PK/PD) approach to dose selection
- Factors driving the use of PK/PD based drug development
- Potential cost benefits

## 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

## 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

## 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

## DRIVERS FOR THE USE OF PK/PD External Factors

- Section 111 of FDAMA provides for:
- “use of PK bridging studies in Pediatric studies of new drugs”

- FDA Modernization Act of 1997 (FDAMA)

## DRIVERS FOR THE USE OF PK/PD External Factors

- 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”

- FDA Modernization Act of 1997 (FDAMA)

## OUTLINE

- Exposure-Response (PK-PD) approach to dose selection
- Factors driving the use of PK-PD based drug development
- Potential cost benefits

## 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

## 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

## 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

## 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

## 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