anti-infective perspective
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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Anti-Infective Perspective
• Anti-Viral Advisory Committee Meeting• July 25th, 2000• Alexander Rakowsky, M.D.
Medical Team Leader/DAIDP/ODE4/CDER
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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
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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
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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
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Basic DivideCONCENTRATION-DEPENDENT
AUC:MIC Peak Conc:MIC
Fluoroquinolones, aminoglycosides
TIME-DEPENDENT
Time>MIC
Beta-lactams, vancomycin
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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
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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
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Time-Dependent
• Major parameter is Time>MIC• Based on animal studies (e.g.,
Craig’s work with AOM)• “Confirmed” by clinical trials
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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)
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Time-Dependentcont
• MIC: – pathogen dependent– resistant strains– inoculum effect, effect of pH on activity,
etc.
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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
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Concentration Dependent
• Major parameters are Peak:MIC and AUC:MIC ratios
• Animal studies conducted• Human studies done with more
recent FQs (Drusano’s work)
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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