Download What is an optimal dosage regimen - Physiologie et Thérapeutique

How to establish a dosage regimen
for a sustainable use of antibiotics in
veterinary medicine
P.L. Toutain
National Veterinary School ;
Toulouse, France
The workshop
• A general presentation by PLT
• Three questions to be discussed in subgroups
animated by team leaders:
– Peter Lees:
• the needs of innovation
– Ted Whittem:
• PKPD, pop kinetics & MCS in antibiotic development
– Marilyn Martinez:
• regulatory hurdles to antibiotic development
"The design of appropriate dosage
regimens may be the single most
important contribution of clinical
pharmacology to the resistance
problem"
Schentag et al. Annals of Pharmacotherapy, 30: 1029-1031
EMEA "Points to consider" July 2000
• Inadequate dosing of antibiotics is probably an
important reason for misuse and subsequent risk
of resistance
• A recommendation on proper dosing regimens for
different infections would be an important part of
comprehensive strategy
• The possibility to produce such a dose
recommendation based on pharmacokinetic and
pharmacodynamic considerations will be further
investigated in one of the CPMP working parties...
Medical consequences of AMR
The antibiotic ecosystem:
one world, one health
Treatment & prophylaxis
Veterinary
medicine
Human medicine
Community
Hospital
Animal feed additives
Agriculture
Plant protection
Environment
Industry
The priorities of a sustainable
veterinary antimicrobial therapy
is related to public health issues,
not to animal health issues
The three (not 2) endpoints to
consider in veterinary medicine
• Efficacy in animal
• No promotion of resistance in
animal (target pathogen)
• No promotion of resistance in
man
But of what resistance
are we speaking?
Prevent emergence of resistance:
but of what resistance?
Target pathogens
Drug efficacy in
animal:
A vet issue
Possible
overuse of
antibiotics
Animal issue
Zoonotics
Drug
efficacy in
man
Natural
eradication
Individual issue
Commensal flora
Resistance gene
reservoir
Global ecological
problem
Risk for
permanent
colonisation
Population issue
What are the animal’s
ecosystems potentially able to
raise public health concerns in
terms of antimicrobial
resistance?
The critical animal ecosystem's in terms of
emergence and spreading of resistance
• Open and large ecosystems
– Digestive tract
– Skin
• Open but small ecosystem
– Respiratory tract
• Closed and small ecosystem
– Mammary gland
Bacterial load exposed to antibiotics
during a treatment
Test
tube
1µg
Infected
Lungs
1 mg
Digestive
tract
2-3Kg
Food chain
Manure
waste
Several tons
Soil, plant….
Biophases & antimicrobial resistance
AB: oral route
Proximal
G.I.T
1-F%
Distal
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
Food chain
Environmental
exposure
Blood
Target biophase
Bug of vet interest
Résistance = lack of efficacy
Résistance = public health concern
Bioavailability of oral tetracyclins
• Chlortetracycline:
– Chickens:1%
– Pigs Fasted or fed: 18 to 19%
– Turkeys:6%
• Doxycycline:
– Chickens:41.3% .
– Pigs :23%
• Oxytetracycline:
– Pigs:4.8%
– Piglets, weaned, 10 weeks of age: by drench: 9%;in
medicated feed for 3 days: 3.7% .
– Turkeys: Fasted: 47.6% ;. Fed: 9.4%
• Tetracycline:
– Pigs fasted:23% .
Biophases & antibiorésistance
Gastrointestinal tract
Proximal
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
Intestinal secretion
Bile
Systemic Administration
Distal
Quinolones
Macrolides
Tétracyclines
Food chain
Environment
Blood
Biophase
Target pathogen
Résistance =public health issue
Résistance = lack of efficacy
Genotypic evaluation of ampicillin resistance:
copy of blaTEM genes per gram of feces
1 E+10
oral route fed
copies/g of feces
1 E+9
1 E+8
oral route fasted
1 E+7
intramuscular route
1 E+6
control group
1 E+5
1 E+4
0
1
2
3
days
4
5
6
7
A significant effect of route of administration on blaTEM
fecal elimination (p<0.001).
Marbofloxacin impact on E. coli in pig intestinal flora
(From P. sanders, Anses, Fougères)
IV
•
•
•
•
IM 3 days
Before treatment : E. coli R (0.01 to 0.1%)
After IV. :Decrease of total E coli , slight increase of E. coli R (4 to 8 %)
Back to initial level
After repeated IM (3d) : Decrease below LoD E. coli (2 days), fast growth (~ 3
106 ufc/g 1 d). E. coli R followed to a slow decrease back to initial level after 12
18 days
• Performance-enhancing antibiotics (old
antibiotics)
– chlortetracycline, sulfamethazine, and penicillin
(known as ASP250)]
• phylogenetic, metagenomic, and quantitative
PCR-based approaches to address the impact of
antibiotics on the swine gut microbiota
• It was shown that antibiotic resistance genes
increased in abundance and diversity in the
medicated swine microbiome despite a high
background of resistance genes in
nonmedicated swine.
• Some enriched genes, demonstrated the
potential for indirect selection of resistance to
classes of antibiotics not fed.
The three (not 2) endpoints to
consider in veterinary medicine
• Efficacy in animal
• No promotion of resistance in
animal (target pathogen)
• No promotion of resistance in
man???????
Innovation: PK selectivity of antibiotics
Proximal
Distal
1-F=90%
Oral
Efflux
F=10%
IM
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
Food chain
Quinolones, macrolides
environment
Blood
Kidney
Biophase
Animal health
Résistance = public health concern
- 22
Question 1:
Peter Lees
• Do we need new antibiotics to fit our
expectation in terms of public health
or rather to encourage the use of old
antibiotics and the promotion of
generics
The right dosage
regimen
What are the elements of a
dosage regimen
• The dose & The dosing
interval
• The treatment duration
–When to start
–When to finish
How to find and to confirm a
dose (dosage regimen)
• Dose titration
– Animal infectious model
• PK/PD
Dose titration
Dose
Response
clinical
Black box
PK/PD
PK
Dose
Body
PD
pathogen
Response
An exposure variable
scaled by MIC
Nice buiatric 2006-27
The dose-titration
ECVPT Toulouse 2009 28
Only the parallel design for antibiotics:
Statistical model
Response NS
• The null hypothesis
*
*
– placebo = D1 = D2 = D3
• The statistical linear model
– Yj = wj + j
Selected dose
Placebo1
2
3 Dose
• Conclusion
– D3 = D2 > D1 > Placebo
The parallel design
• Advantages
– easy to execute
– total study lasts over one period
– approved by Authorities
• Disadvantages
– "local information" (response at a given dose does not
provide any information about another dose)
– no information about the distribution of the individual
patient's dose response.
The dose-titration:
experimental infectious model
• Severe
• not representative of the real world
– Prophylaxis vs. metaphylaxis vs. curative
• power of the design generally low for
large species
• influence of the endpoints
Antibiotic dosage
regimen based on PKPD and population PK
concepts
Measuring exposure
and response in
PK/PD trial
It has been developed surrogates
indices (predictors) of antibiotic
efficacy taking into account MIC (PD)
and exposure antibiotic metrics (PK)
Practically, 3 indices cover all situations:
•AUC/MIC
•Time>MIC
• Cmax/MIC
PK/PD predictors of efficacy
• Cmax/MIC : aminoglycosides
• AUC/MIC : quinolones, tetracyclines, azithromycins,
• T>MIC : penicillins, cephalosporins, macrolides,
Cmax
Concentrations
Cmax/MIC
AUIC =
AUC
MIC
MIC
T>CMI
24h
Time
Nice buiatric 2006-35
Appropriate PK/PD indices for the different
antibiotics according to their bactericidal properties
Bactericidal pattern
Type I
Concentration
dependant &
persistent effect
Type II
Time-dependent
and no persistent
effect
Type III
Time-dependent
and dosedependent
persistent effect
Antibiotics
Therapeutic goal
PKPD
indices
Aminoglycosides
Fluoroquinolones
To optimize
plasma
concentrations
Cmax/MIC
24h-AUC/MIC
Penicillins
Céphalosporins
To optimize
duration of
exposure
T>MIC
Macrolides
Tétracyclines
To optimize
amount (doses)
24h-AUC/MIC
What is the appropriate
magnitude of PK/PD indices
to guarantee efficacy i.e. how
establish PK/PD breakpoint
values:
1. To optimize efficacy
2. To minimize resistance
towards the target pathogen
Breakpoint values in veterinary
medicine
• Starting values
– From human medicine
– From in vitro/ex vivo (tissue cage)
experiments
• In vivo experimental determination
Nice buiatric 2006-38
First step of the PKPD approach
• To establish experimentaly the numerical
value of the PKPD surrogate that garantee
a Probability of cure (POC) or any other
relevant endpoint (bacteriokogical cure…)
– E. g what is the numerical value of the
AUC/MIC for a new quinolone to obtain more
than 90% of clinical success in pigs treated
metaphylactically for a lung condition?
Nice buiatric 2006-39
A working example
Your development project
• You are developing a new antibiotic in pigs
(e.g. a quinolone) to treat respiratory
conditions and you wish to use this drug in
for metaphylaxis (control)
• collective treatment & oral route
Questions for the developers
• What is the optimal dosage regimen for
this new quinolone for metaphylaxis ings
• To answer this question, you have, first, to
define what is an “optimal dosage
regimen”
MonteCarlo-Orlando06 42
Step 1: Define what is an
optimal dosage regimen
What is an optimal dosage regimen ?
1. Efficacy :
– it is expected to cure at least 90% of pigs
– “Probability of cure” = POC = 0.90
•
We know that the appropriate PK/PD index for
that drug (quinolone) is AUC/MIC
•
We have only to determine (or to assume) its
optimal breakpoint value for this new quinolone
What is an optimal dosage regimen ?
2. Emergence of resistance
– The dosage regimen should avoid the
mutant selection window (MSW) in at
least 90% of pigs
Plasma concentrations
The selection window
hypothesis
Mutant prevention concentration (MPC)
(to inhibit growth of the least susceptible, single step mutant)
Mutant Selection
window
All bacteria
inhibited
MIC
Selective concentration (SC)
to block wild-type bacteria
Growth of only the
most resistant
subpopulation
Growth of all
bacteria
Two endpoints for an optimal dosing
regimen
1. Probability of “cure” = POC = 0.90
2. Time out of the MSW should be higher
than 12h (50% of the dosing interval)
in 90% of pigs
Step 2: Determination
of the AUC/MIC clinical
breakpoint value for the
new quinolone in pigs
Determination of the PK/PD
clinical breakpoint value
• Dose titration in field trials :
– 4 groups of 10 animals
– Blood samples were obtained
– MIC of the pathogen is known
 Possible to establish the relationship
between AUC/MIC and the clinical
success
MonteCarlo-Orlando06 49
AUC/MIC vs. POC: Metaphylaxis
1
0.9
0.8
POC
POC
0.7
Data points were derived by forming
ranges with 6 groups of 5 individual
AUC/MICs and calculating mean
probability of cure
0.6
0.5
0.4
0.3
0.2
10 Control pigs (no drug)
0.1
0
0
50
100
AUC/MIC
AUC/MIC
150
200
Probability of cure (POC)
• Logistic regression was used to link measures of drug
exposure to the probability of a clinical success
POC 
Dependent
variable
1
1  e a bf  AUC MIC 
Placebo
effect
sensitivity
Independent
variable
2 parameters: a (placebo effect) & b (slope of the exposure-effect curve)
Metaphylaxis
(collective treatment)
1.2
1
POC
0.8
0.6
0.4
0.2
0
0
50
100
150
AUC/MIC
1
1  e 0.4050.0325 AUC MIC 
200
Conclusion step 2
Metaphylaxis
Placebo effect
40%
Breakpoint value of
AUC/MIC
to achieve a
POC=0.9
80h
Step 3
What is the dose to be
administrated to guarantee
that 90% of the pig
population will actually
achieve an AUC/MIC of 80
for an empirical (MIC
unknown)
Determination of a dose for a quinolone
Breakpoint value
e.g. 80h
PD
 AUC 
Clearance (per hours)  
  MIC
MIC  BP

Dose 
fu  F %
Bioavailability
Free fraction
Solving the structural model to compute
the dose for my new quinolone
• With point estimates
– (mean, median, best-guess value…)
• With range estimates
– Typically calculate 2 scenarios: the best case & the
worst case (e.g. MIC90)
– Can show the range of outcomes
• By Monte Carlo Simulations
– Based on probability distribution
– Give the probability of outcomes
Computation of the dose with point
estimates (mean clearance and F%, MIC90)
BP: 80
MIC50=1µg/mL
9mL/Kg/h
 AUC 
Clearance (per hours)  
  MIC
 MIC  BP
Dose 
F%
Dose: 1.44mg/kg
Bioavailability=50%
Computation of the dose with point estimates
(worst case scenario for clearance and F%, MIC90)
BP: 80
MIC90=2µg/mL
15mL/Kg/h
 AUC 
Clearance (per hours)  
  MIC
 MIC  BP
Dose 
F%
Bioavailability= 30%
Dose: 8.0 (vs. 1.44) mg/kg
MonteCarlo-Orlando06 58
Computation of the dose using Monte Carlo
simulation
(Point estimates are replaced by distributions)
Log normal distribution: 9±2.07 mL/Kg/h
Observed distribution
BP
metaphylaxis
Clearance  80  MIC
Dose 
F%
Dose to POC=0.9
MonteCarlo-Orlando06 Uniform distribution: 0.3-0.70
59
• An add-in design to help
Excel spreadsheet
modelers perform Monte
Carlo simulations
• Others features
– Search optimal solution (e.g.
dose) by finding the best
combination of decision
variables for the best possible
results
Metaphylaxis:
dose to achieve a POC of 90% i.e. an AUC/MIC of 80
(empirical antibiotherapy)
Dose distribution
MonteCarlo-Orlando06 61
Computation of the dose: metaphylaxis
(dose=2mg/kg from the dose titration)
PK/PD Model
Dose (mg/kg)
Mean
1.44
Worst case scenario
8.00
Monte Carlo
3.803
(empirical antibiotherapy)
Sensitivity analysis
• Analyze the contribution of the different variables
to the final result (predicted dose)
• Allow to detect the most important drivers of the
model
Sensitivity analysis
Metaphylaxis, empirical antibiotherapy
Contribution of
the MIC
distribution
MonteCarlo-Orlando06 64
The second criteria to
determine the optimal dose:
the MSW & MPC
Kinetic disposition of the new quinolone for the
selected metaphylactic dose (3.8 mg/kg)
(monocompartmental model, oral route)
Log normal distribution: 9±2.07 mL/kg/h
F%
Uniform distribution: 0.3-0.70
Slope=Cl/Vc=0.09 per h (T1/2=7.7h)
concentrations (µg/mL)
concentrations
8
MPC
7
6
5
MIC
4
Série1
3
2
MSW
1
0
0
5
10
15
Time (min)
20
25
30
Computation of the dose (mg/kg):
for given target attainment rates (TAR) for efficacy and to
prevent selection of mutants
Monte Carlo
curative
Efficacy
3.8
To guarantee
T>MPC in 90% of
pigs for 50% the
dosage interval
5.9
Question 2
Ted Whittem
• What is the place of PK/PD, population
kinetic and Monte Carlo Simulations in the
rational development of a new antibiotic:
the pro & cons, limits….
4-The right duration
When to start a treatment?
The different usages of antibiotics
Disease
health
Antibiotic consumption
Therapy
Metaphylaxis
(Control)
Pathogen load
Prophylaxis
(prévention)
Growth
promotion
Only a risk factor
High
Small
No
NA
MICs estimated with different inoculmum densities,
relative to that MIC at 2x105
Ciprofloxacin
Gentamicin
Linezolid
Oxacillin
Daptomycin
Vancomycin
The inoculum effect and Very
Early Treatment (VET)
• Efficacious dosage regimen is different
when the pathogen load is large, low or
null
• Treatment should start as early as
possible
What was demonstrated
• For a same dose of marbofloxacin, early
treatments (10 hours after the infection) were
associated to
– more frequent clinical cure
– more frequent bacteriological cure
– less frequent selection of resistant bacteria
than late treatments (32 hours after the infection)
Early administrations were more favourable
than late administrations
Metaphylaxis and Very Early
Treatment (VET)
• I suggest to replace metaphylaxis by VET
because metaphylaxis convey negative
values
– Confusion with mass treatment,
– Confusion with prophylaxis
When to finish a treatment?
• ASAP
• Should be determined in clinics
• Should be when clinical cure is actually
achieved
• Should not be a hidden prophylactic
treatment for a possible next infectious
episode
Question 3
Marilyn Martinez
• What are the hurdles to the development of a new
antibiotic or to the revisit an old antibiotic
– Possibility or not to have several dosage regimen
(curative vs. control VS prophylaxis)
– Protection of innovation
– Regulatory climate
– Acceptance or not of PK/PD, Pop, MCS….
– Validity of susceptibility testing and development of
appropriate breakpoints
– Hypothesis to test for clinical trial: non inferiority or
superiority?
– ….
Conclusion
• You have 25 minutes to discuss theses 3
questions