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 DivideCONCENTRATION-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-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)

Time-Dependentcont

• MIC: – pathogen dependent– resistant strains– inoculum effect, effect of pH on activity,

etc.

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

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 Dependentcont

• 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

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

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

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

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