1. Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

2. Why Interest in Pharmacodynamics? Always occurs when there is narrow difference between MICs and obtainable drug concentrations - early days of penicillin in 1940s (low doses used) - appearance of Pseudomonas infections in 1960s and 1970s (high MICs) - appearance of resistant Streptococcus pneumoniae and other bacteria in 1990s

3. Applications of PK-PD Optimize dosage regimens - once-daily dosing of aminoglycosides - prolonged or continuous infusion of beta-lactams Establish susceptibility breakpoints - new NCCLS breakpoints with oral beta-lactams and with ceftriaxone/cefotaxime for pneumococci Preventing the emergence of resistance - with fluoroquinolones and gram-negative bacilli

4. PK/PD Parameters versus Emergence of Resistance for Fluoroquinolones Resistance Developed 24-Hr AUC/MIC P. aeruginosa Other GNB <100 - Monotherapy 80% 100% >100 – Monotherapy 33% 10% Combinations 11% 0% 25% 12% Thomas et al. AAC 42:521, 1998

5. Applications of PK-PD Guideline development - CDC guidelines for pneumonia and otitis media - Sinus and Allergy Health Partnership guidelines for sinusitis Formulary decisions - based on local or regional susceptibility data

6. Application of PK-PD for New Drug Development Dose Selection for Phase 2/3 Studies - in vitro and animal studies to identify PK-PD target for efficacy - phase 1 studies to determine which doses reach target with high probability - mostly with antibacterials; rarely with antifungals Susceptibility Breakpoint Selection - required by NCCLS by M23 (1 of 4 parameters used for breakpoint selection) - FDA – variable use

7. Application of PK-PD for New Drug Development PK-PD studies in phase 2/3 clinical trials - optimal sampling techniques - interest in including “time to events” - statistical strategies to model both clinical and microbiological outcomes - bacteriologic cure usually harder to obtain than clinical cure

8. Relationship Between 24-Hr AUC/MIC and Efficacy of Ciprofloxacin in 64 Patients with Serious Bacterial Infections Forrest et al. AAC 37:1073, 1993

9. PK-PD Studies in Phase 2/3 Clinical Trials Increases complexity of study Increases cost No established benefit with regulatory agencies Can such studies reduce the number of patients needed for efficacy trials ? - used for a fluoroquinolone to reduce number of cases for inclusion of penicillin-resistant pneumococci in label

10. Dose Selection What is the PK-PD indice that best determines efficacy? Requires in vitro or animal models What is the magnitude of the PK-PD indice required for efficacy? Should be based on free drug levels and linked to survival in animal models How do neutrophils effect the magnitude of the PK-PD indice? Does the magnitude vary with different organisms especially resistant strains? Does the magnitude vary with different sites of infection

11. Correlation of Serum Concentrations with Sites of Infection Serum Interstitial fluid Fluid Collections (sinusitis, AOM) Abscess ELF ( macrolides; vanco, dapto) CSF Intracellular fluid Urine Good Poor

12. Dose Selection What is the magnitude of the PK-PD indice required to prevent the emergence of resistance? Can nontoxic doses of the drug in humans reach the magnitude of the PK-PD indice required for efficacy and for prevention of resistance with a high probability? Should be based on free drug concentrations