# Presentation: 936460

## Anti-Infective Perspective

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

## 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**

## 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**

##  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**

## Basic Divide

***CONCENTRATION-DEPENDENT***
**AUC:MIC **
**Peak Conc:MIC**
**Fluoroquinolones, aminoglycosides**

***TIME-DEPENDENT***
**	****	****Time>MIC**
**	****	****Beta-lactams, ****	****vancomycin**

## 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**

## 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**

## Time-Dependent

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

## Time-Dependentcont

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

## Time-Dependentcont

**MIC: **
**pathogen dependent**
**resistant strains**
**inoculum effect, effect of pH on activity, etc.**

## Time-Dependentcont

**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**

## Concentration Dependent

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

## Concentration Dependentcont

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

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## Augmentincont

**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**

## Augmentincont

**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**

## Augmentincont

**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**

## 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**