Pop-PK meta-analysis

Evidence
E
id
synthesis
th i and
d
meta-analysis:
y
an example
p of the
challenges based on dose selection
for antibiotics.
antibiotics
Dr Charlotte Barker
GRiP Clinical Research Fellow
Paediatric Infectious Diseases Research Group
p
St George’s, University of London
GRiP Workshop on Extrapolation and Evidence Synthesis
Glasgow, 11th June 2013
Overview
•
Background
•
Example: Piperacillin
•
Translating PK studies: grading the evidence
•
Pop-PK
p
reporting
p
g
•
PK meta-analysis
•
Conclusions
PK = pharmacokinetic(s) Pop‐PK = population pharmacokinetic(s)
1a
©2011 by British Medical Journal Publishing Group
BMJ 2011; 343: d7803.
Timeline of changes in the single oral child and adult dose of penicillin V
1b
BMJ 2011; 343: d7803.
1c
First considerations
What is the evidence behind current paediatric
dosing recommendations?
?
What is your nationally accepted reference
source for p
paediatric dosing?
g
SPCs, paper formulary, electronic formulary...
2a
SPC = Summary of Product Characteristics
British National Formulary for Children
Antimicrobial dosing
g recommendations
• age-bands
• weight-bands
• weight-based calculations
Rationale? Evidence?
Confusion….?
2b
BNFC = British National Formulary for Children www.bnf.org
Evidence-based changes to practice
What evidence is necessary to change current
paediatric
di t i d
dosing
i recommendations?
d ti
?
Who decides?
2c
The paediatric PK pathway
Regulators
SPC
Formulary
committee
Recommendation
PK studyy
Complicated by off-label/unlicensed usage of medicines in children
3a
Paediatric PK methods: old and new
Traditional PK
3b
Population PK studies
Rich sampling
Sparse sampling
Ethical issues
Inter-individual variability
Practical challenges
Explain drug disposition
Recruitment issues
Modelling and simulation (M&S)
Generalisability varies
Now standard practice
Paediatric PK drugs: old and new
3c
Old drugs
New drugs
Off patent
Off-patent
Expensive to develop
Known dosing recommendations
PIPs complex
Routine practice
Varying paediatric need
Established for years
What risk is acceptable?
Not commercially attractive
Economic influence
P di t i PK d
Paediatric
data
t llacking
ki
St d numbers
Study
b
PD & safety data often sparse
Role of modelling and simulation
PD = pharmacodynamic(s) PIP = Paediatric Investigation Plan
Antimicrobial-specific
Antimicrobial
specific issues
Where

is the bug vs where is the drug?
 Drug concentration in tissue of interest?
Toxicity
Supratherapeutic
Target concentrations
T ti disease
Treating
di
Subtherapeutic
Driving resistance
4a
Antimicrobial pharmacodynamics
 l t
-lactams
fluoroquinolones
aminoglycosides
4b
Curr Opin Infect Dis. 2012; 25(3): 235‐42.
Antimicrobial pharmacodynamics (PD)
Pathogen-specific PD:
•
MICs,
•
Susceptibility breakpoints
breakpoints,
•
Resistance
Breakpoints
4c
validated in paediatric population?
MIC = Minimum inhibitory concentration
Monte Carlo simulations:
Variability
V
i bilit off PK parameters
t
used
d tto simulate
i l t
multiple
p concentration–time curves
(Typical simulation 5000–10000 cycles)
4d
Host
Clinical
outcome
Bug(s)
4e
Drug(s)
Antimicrobial PD (2)
PD Endpoints:
Microbiological success
Clinical outcomes
Suppression
pp
of emergence
g
of resistance
4f
Antimicrobial PD (3)
Syndrome-based dosing recommendations
e.g. community-acquired pneumonia
4g

Guidelines for empiric therapy

Need to consider local AMR patterns
p

Consideration of antibiograms etc.
AMR = antimicrobial resistance Overview
•
Background
•
Example: Piperacillin
•
Translating PK studies: grading the evidence
•
Pop-PK
p
reporting
p
g
•
PK meta-analysis
•
Conclusions
Piperacillin/tazobactam
5a
www.bnf.org
SPC: Piperacillin/tazobactam
Paediatric population (2-12 years of age)
Infections: dose per body
y weight
g for patients 2-12 y
years
of age by indication or condition:
Dose per weight and frequency
Indication / condition
80mg
g Piperacillin
p
/ 10mg
g Tazobactam
per kg body weight / every 6 hours
Neutropenic
p
children with fever
suspected to be due to bacterial
infections*
100mg Piperacillin / 12.5mg
Tazobactam per kg body weight /
every 8 hours
Complicated intra
intra-abdominal
abdominal
infections*
* Not to exceed the maximum 4 g / 0.5 g per dose over 30 minutes.
5b
Source: http://www.medicines.org.uk/emc/medicine/2239/SPC/ SPC: Piperacillin/tazobactam
Use in children aged below 2 years
The safety and efficacy of Tazocin in children
0- 2 years of age has not been established.
“No
o data from
o co
controlled
t o ed
clinical studies are available”
5c
Source: http://www.medicines.org.uk/emc/medicine/2239/SPC/ Piptazobactam: PK studies incl. <2yrs
5d
1983
• preadolescent
d l
t children
hild
1986
• newborns
1992
• newborns
1994
• infants and children
2004
• very low birth weight infants
2006
• neonates ((sepsis)
p )
2007
• <25 months (paediatric cancer)
References in appendix
Piptazobactam: off-label concerns
5e
Br J Clin Pharmacol. 2008 Jun;65(6):971‐2. Overview
•
Background
•
Example: Piperacillin
•
Translating PK studies: grading the evidence
•
Pop-PK
p
reporting
p
g
•
PK meta-analysis
•
Conclusions
Translating
g PK studies
•
Translating
g neonatal and p
paediatric p
pop-PK
p
to
dosing recommendations
6a
•
E id
Evidence:
Q
Quality?
li ? Q
Quantity?
i ?
•
Consider metronidazole as an example:
p
Metronidazole
6b
Pediatrics. 2011; 127(2): e367‐74.
BNFC May 2013 6c
Curr Opin Infect Dis. 2012; 25(3): 235‐42. 6d
Curr Opin Infect Dis. 2012; 25(3): 235‐42. 6e
Curr Opin Infect Dis. 2012; 25(3): 235‐42. Original source: www.cebm.net
Overview
•
Background
•
Example: Piperacillin
•
Translating PK studies: grading the evidence
•
Pop-PK
p
reporting
p
g
•
PK meta-analysis
•
Conclusions
Pop-PK publications in journals
•
No standardised reporting
p
g requirements
q
•
Heterogeneous presentation of:
• Study
S d d
design
i
• Conduct
• Analysis
y
• Conclusions
7a
Pop-PK Model
Piperacillin clearance
CL ((L/h)) = 0.479 x (weight)
(
g )0.75 x 0.5/serum creatinine
7b
Ther Drug Monit. 2012; 34(3): 312-9.
Piperacillin Pop-PK: scavenged sampling
7c
Ther Drug Monit. 2012; 34(3): 312-9.
Pop-PK Model
Piperacillin clearance
Central CL ((L/h):
)
7d
CL = θ1(BW/2.76)
(
)θ5((PNA/6))θ6
Eur J Clin Pharmacol. 2013 Jun;69(6):1223-33.
Pop-PK Model
Piperacillin dosing
PD Target: f%T >MIC% > 50 %
Infant BW 1 kg and PNA 3 days
Dose: 10 mg/kg every 8 h
p(0.95) adequate protection vs Asia-Pacific ESBL E. coli
If BW 4.5 kg and PNA 7 days
Dose: 100 mg/kg given every 6 h
to attain the same result
7e
Eur J Clin Pharmacol. 2013 Jun;69(6):1223-33.
7f
Eur J Clin Pharmacol. 2013 Jun;69(6):1223-33.
Category
Sub-category
Item
Data
Study population
Total number of subjects and
observed concentrations used
in the analysis
Cohort demographics
Distribution of samples (times
and number per participant)
Raw data plots
Internal/external validation
datasets
Study drop-out details
(time/number)
Missing data details: doses,
sample times, covariates
Subjects not included in
analysis
Outlier handling details
Covariate correlation
Base model
Parameter estimates and
standard errors for final model
(not base model)
Inter-/intra-individual
variability models
Residual variability model
Goodness of fit (GOF) plots
(final model only)
Covariate relationship
screening plots
C
Covariate
i t model
d lb
building
ildi
steps and selection
Final covariate model
Final model with parameter
estimates (and standard
errors/confidence
/
fid
intervals)
i t
l )
Model diagnostics: visual
predictive checks and
bootstrapping results with
95% confidence intervals
Study samples
Raw data
Validation
Subject dropouts
Missing data
Model building
Subjects
excluded
Outliers
Covariates
Base model
Parameters
Variability
Goodness of fit
Covariate
selection
Final model
Model evaluation
8a
Model evaluation
procedures
3
4
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Barker et al.. ESDP poster 2013
8b
http://www.consort-statement.org/
Pop-PK publications in journals
•
CONSORT-style
y agreement
g
for standardizing
g
pop-PK reporting requirements?
•
8c
P di i specific
Paediatric
ifi components
Overview
•
Background
•
Example: Piperacillin
•
Translating PK studies: grading the evidence
•
Pop-PK
p
reporting
p
g
•
PK meta-analysis
•
Conclusions
Systematic Review of PK(/PD) studies, including
robust
b t meta-analysis
t
l i off raw data
d t based
b d on
prospective data warehousing and common
definitions of all relevant variables
9a
Curr Opin Infect Dis. 2012; 25(3): 235‐42. PK meta-analysis
•
Synthesising
y
g traditional ((rich)) PK data and
sparse pop-PK data
•
9b
Accepted methodology?
9c
Meta-analytical
Meta
analytical methods
Traditional meta-analysis
• Summary
y data of different
studies
9d
IPD meta-analysis
• Complete
p
datasets of
different studies
•
Obtained from publications
•
Obtained from authors
•
Combined and analysed
•
Pooled into one dataset
 analysed simultaneously
•
Correct for variability
between studies
Meta-analytical
Meta
analytical methods (2)
Pooling
P
li participants:
ti i
t nott a valid
lid approach
h tto
meta-analysis http://www.cochrane-net.org/openlearning/html/mod12-2.htm
IPD meta-analysis: a specific type of SR.
IPD SRs offer benefits particularly relating to the
quality
q
y of data and the p
possible types
yp of
analyses.
For this reason they are considered to be a ‘gold
standard’ of systematic review
standard
review.
http://handbook.cochrane.org/ Chapter 18: Reviews of individual patient data
9e
9f
Pop-PK meta-analysis
•
No formal methodology
gy
•
Individual patient data (‘IPD’) preferable
•
Li i i
Limitations
Heterogeneity in multiple aspects: study design
design,
population
p
p
demographics,
g p
laboratory
y aspects
p
(biopharmaceutical assays)...
10a
Piptazobactam Neonatal Pop-PK Models
1 compartment model
CL (L/h) = 0.479 x (weight)0.75 x 0.5/serum creatinine
Residual variability: proportional error model
Ther Drug Monit. 2012; 34(3): 312-9.
10b
Piptazobactam Neonatal Pop-PK Models
1 compartment model
CL (L/h) = 0.479 x (weight)0.75 x 0.5/serum creatinine
Residual variability: proportional error model
2 compartment
t
t model
d l
Central CL (L/h) = θ1(BW/2.76)θ5(PNA/6)θ6
Residual
id l variability:
i bili proportional
i l error model
d l
CL = clearance BW = birth weight
PNA = postnatal age
10b
Ther Drug Monit. 2012; 34(3): 312-9.
Eur J Clin Pharmacol. 2013 Jun;69(6):1223-33.
“Successfully transformed 6 non-compartment
model
d l PK parameters
t
from
f
10 publications
bli ti
into
i t
5 compartment model PK parameters”
(midazolam)
10c
10d
Overview
•
Background
•
Example: Piperacillin
•
Translating PK studies: grading the evidence
•
Pop-PK
p
reporting
p
g
•
PK meta-analysis
•
Conclusions
Conclusions
Synthesising
y
g the evidence to achieve dose
selection for antibiotics will need:
(1) Agreement on evidence required to change
f
formulary
l
recommendations
d i
and
d SPC
SPCs
(2) Consensus on paediatric pop-PK reporting
((3)) Consensus on PK meta-analytical
y
methodology
gy
(traditional and population studies)
Conclusions
Regulators
Industry
Paediatricians
Academia
Pharmacists
Public
Pharmacologists
Practitioners
Regulators
Industry
Paediatricians
Academia
Pharmacists
Pharmacolo
Translation
PK/PD
research
Public
Patient
benefit
Practitioners
Future
(1) Methodological research: IPD PK meta-analysis
(2) Paediatric antimicrobial PK/PD studies
(3) C
Central
t ld
data
t repositories
it i
(4) V
Validate
lid
PD targets iin children
hild
 Review +/- simplify dosing recommendations
Acknowledgements
Global Research in Paediatrics
PhD Supervisors: Prof. Mike Sharland, Dr. Joe Standing,
Dr. Mark Turner, Prof. Atholl Johnston
London Pharmacometrics Interest Group
SGUL Paediatric Infectious Diseases Research Group
References (1)
1. BMJ
2011; 343:d7803
2. BNF
for Children. http://bnfc.org/bnfc/
3. Curr
Opin Infect Dis. 2012; 25(3): 235-42.
4. http://www.medicines.org.uk/emc/medicine/2239/SPC/
5. Br
J Clin Pharmacol. 2008 Jun;65(6):971-2.
( )
6. http://www.thecochranelibrary.com/view/0/CochraneMetho
ds html
ds.html
7. Ther
8. Eur
Drug Monit. 2012; 34(3): 312-9.
J Clin Pharmacol.
Pharmacol 2013 Jun;69(6):1223-33.
Jun;69(6):1223 33
9. http://www.consort-statement.org/
References (2): Piptazobactam use in children <2yrs
1.
2.
3.
4.
5.
6.
7
7.
Thirumoorthi MC, Asmar BI, Buckley JA, Bollinger RO, Kauffman RE, Dajani AS.
Pharmacokinetics of intravenously administered piperacillin in preadolescent children. J
P di t 1983;
Pediatr.
1983 102(6):
102(6) 941
941-6.
6
Kacet N, Zaoui C, Roussel-Delvallez M, Dubos JP, Martin GR, Lequien P. [Piperacillin in
the newborn infant. A clinical and pharmacologic study]. Presse Med. 1986; 15(46):
2339 41
2339-41.
Kacet N, Roussel-Delvallez M, Gremillet C, Dubos JP, Storme L, Lequien P.
Pharmacokinetic study of piperacillin in newborns relating to gestational and postnatal
age.
g Pediatr Infect Dis J. 1992;; 11(5):
( ) 365-9.
Reed MD, Goldfarb J, Yamashita TS, Lemon E, Blumer JL. Single-dose
pharmacokinetics of piperacillin and tazobactam in infants and children. Antimicrob
Agents Chemother. 1994; 38(12): 2817-26.
Berger A, Kretzer V, Apfalter P, Rohrmeister K, Zaknun D, Pollak A. Safety evaluation of
piperacillin/tazobactam in very low birth weight infants. J Chemother. 2004; 16(2): 16671.
Flid l Ri
Flidel-Rimon
O Friedman
O,
Fi d
S
S, Leibovitz
L ib it E,
E Shi
Shinwellll ES
ES. Th
The use off
piperacillin/tazobactam (in association with amikacin) in neonatal sepsis: efficacy and
safety data. Scand J Infect Dis. 2006; 38(1): 36-42.
Simon A
A, Lehrnbecher T,
T Bode U
U, Groll AH,
AH Tramsen L,
L Wieland R
R, et al
al. Piperacillintazobactam in pediatric cancer patients younger than 25 months: a retrospective
multicenter survey. Eur J Clin Microbiol Infect Dis. 2007; 26(11): 801-6