Anti-Infective Perspective

1. Anti-Infective Perspective • Anti-Viral Advisory Committee Meeting • July 25th, 2000 • Alexander Rakowsky, M.D. Medical Team Leader/DAIDP/ODE4/CDER

2. Proper Perspective • Focus can be on: new drug development versus changes in dosing/formulation/combinations with approved drugs • Focus can be on: systemic agents versus topical agents • Looking at approved, systemic agents in this presentation

3. Documents/Guidances • 1992 Anti-Infectives Points to Consider and also the IDSA/FDA guidances • Recent re-writes of guidance for various indications • Clinical Effectiveness Document • Again, focus here is on approved drugs with changes in dosing/formulation/combinations which lead to a NON-bioequivalent state

4. Outline of this Talk • “Don’t kill the messenger” • Brief primer on PK/PD parameters used in antibacterials (HFD-520 and HFD-590) • Discussion of how these parameters have or could be used • Example

5. CONCENTRATION-DEPENDENT AUC:MIC Peak Conc:MIC Fluoroquinolones, aminoglycosides TIME-DEPENDENT Time>MIC Beta-lactams, vancomycin Basic Divide

6. MIC????? • “Mean inhibitory concentration” • MBC is similar concept • Based on standardized in vitro work using specified conditions, growth media, concentrations, nutrient additives for fastidious organisms, etc. • Reproducibility

7. MIC?cont • Difficulty is in interpretation of MIC (S/I/R) • Based on achievable drug levels (ADME parameters) • Clinical data is of importance • Defined after discussions by committee (NCCLS) or review (FDA) • Even then, occasional disagreement

8. Time-Dependent • Major parameter is Time>MIC • Based on animal studies (e.g., Craig’s work with AOM) • “Confirmed” by clinical trials

9. Time-Dependentcont • “Time >” dependent on ADME parameters: • Cmax achieved • distribution of drug (e.g. serum versus tissue, protein binding, etc.) • half-life of drug (metabolism, excretion)

10. Time-Dependentcont • MIC: • pathogen dependent • resistant strains • inoculum effect, effect of pH on activity, etc.

11. Time-Dependentcont • Animal and human studies: • T>MIC in 40-60% range is PREDICTIVE of clinical success • 100% correlation? NO • Varies also among members of the same class • Other variables which need to be accounted for but not as well defined: Post-antimicrobial effect

12. Concentration Dependent • Major parameters are Peak:MIC and AUC:MIC ratios • Animal studies conducted • Human studies done with more recent FQs (Drusano’s work)

13. Concentration Dependentcont • Still dependent on ADME parameters • absorption • distribution • local levels/penetration • local effects (e.g., pH) • Clinical studies predictive, but again, not 100% correlations.

14. Conclusions so far • Variables are based on ADME ranges • Work has shown good predictiveness but not 1:1 correlation • Variability in the MICs • Most work done on beta-lactams and FQs

15. So What is the Role of PK/PD? • Several recent meetings to discuss: • DAIDP Advisory Committee: 7/98 and 10/98 • July 1998: FDA/Industry meeting • March 1999: FDA/ISAP Workshop • ISAP: The International Society of Anti-Infective Pharmacology

16. Other Difficulties Raised • Emphasis has been on effectiveness,not safety • Most work done with single drug/bug • Acute models used (chronic use/chronic illness not well studied) • Moving targets (resistance development), esp. with chronic use, use over time

17. Is All Lost? • Overall, positive impressions • PK/PD for certain antimicrobial drug classes is well worked out • Models used (both animal and human) are improving greatly • Can be seen, in the proper context, as strong supportive evidence

18. Coming Full Circle • Augmentin 7:1 NDAs (submitted in 1994/1995) • Adults: 500 mg tid to 875 mg bid of amoxicillin and 250 mg tid to 500 mg bid • Pediatrics: 40/mg/kg/day divided tid to 45 mg/kg/day divided bid of amoxicillin • In all formulations, clavulanic acid amount remained the same. Led to 1/3rd less daily clavulanate

19. Augmentin (cont) • In all settings, AUC and half-life comparable between new and old dosing regimens • Cmax higher by 50-80% in bid dosing regimens • T>MIC lower in bid regimens • on average, bid regimens with 10 hours (out of 24) • on average, tid regimens with 11 hours (out of 24) • concerns also with 1/3rd lower beta-lactamase inhibitor activity

20. Augmentincont • Post-antibiotic and post-beta-lactamase inhibitor effects were studied and proposed • Animal studies showed comparable efficacy rates for the bid and tid dosing regimens • Due to concerns with lower T>MIC and clavulanic acid, clinical studies were asked for

21. Augmentincont • One study per indication was conducted (historically, two would have been required) • NDAs were approved based on: • in vitro microbiology and animal work • PK/PD data from humans • one adequate, well-controlled study per indication • agreement to study as q12 not bid

22. Augmentincont • Ultimately these NDAs were approved with approximately 50% less subjects enrolled then historically required • See this as a good example of where/how PK/PD parameters can be used

23. Conclusions • Certain parameters/drug classes well worked out • Still issues with variability (with ADME parameters, MICs, local effects, etc.) • Multiple meetings held where, at this time, PK/PD is seen as strong supportive evidence but that for reasons listed, should not be used in lieu of clinical evidence