Transcript they don`t

Pharmacokinetic and
pharmacodynamic considerations for
pediatric antifungal dosing
OR
How the cauliflower had its revenge
Three areas
• Pharmacometric problem
– Designing pediatric regimens to produce drug
exposure that matches adults
• Quantifying and managing variability
– Ideas of control and dosage individualization
• Understanding pharmacodynamic differences
– Placed in a drug regulatory framework
Why are pediatric dosages
frequently different to adults?
Is drug exposure in adults and
children receiving x mg/kg the
same?
The answer is NO in the majority
of cases
But why- especially when we think
weight is such a good measure of
size?
Pediatric pharmacology requires an
understanding of the biology of size
Metabolic Rate  Weight 0.75
Tissues have a supply problem:
implications for drug clearance
• Hepatic vasculature competes for space with
hepatocytes
• But, the most efficient transport system takes up a
fixed % of volume
• So,
– if number of cells doubles +
– the most efficient transport system is used
– a more sparsely distributed supply network results
• A more sparsely supplied network is less efficient
In summary, therefore
• A bigger organ is less efficient per unit size
• A smaller organ is more efficient per unit size
• For drug clearance, a bigger liver has more
capacity to clear drug, but it is less efficient
per unit size
A myth: children have higher clearancesthey don’t
2 .0 0
1 .6 0
Cl earance (L/ h)
(L/h)
Clearance
n=119
Children
1 .2 0
Neonates
0 .8 0
0 .4 0
0 .0 0
0 .1
1
10
W e i g h t (kg)
(k g )
Weight
100
200
Log-log plot shows a straight line
1000
Clearance (L/h)
Cl earance (L/ h)
100
Slope= 0.75
10
Children
Neonates
1
0 .1
0 .0 1
0 .1
1
10
W e i g h t (k g )
Weight
(kg)
100
1000
But, smaller children do have higher
weight-corrected clearances
0 .1 2
Cl earance (L/
h/ kg)
(L/h/kg)
Clearance
Neonates
0 .1 0
0 .0 7
Children
0 .0 5
0 .0 2
0 .0 0
0 .1
1
10
W e i g h t (k g )
Weight
(kg)
100
200
Administering a weight-based dosage
results in different drug exposures
300
Children
(mg•kg/ h)
(mg·h/L)
AUCA UC
240
Neonates
180
120
60
0
0 .1
1
10
W e i g h t (kg)
(k g )
Weight
100
200
Fact Sheet: Triazoles (see Lestner et al
British J Clin Pharmacology)
•
•
•
•
Fluconazole 6-12 mg/kg
Voriconazole 9 mg/kg load + 8 mg/kg q12h
Posaconazole adult regimen down to 8 yrs
Itraconazole 2.5-5 mg/kg q12h
Fact Sheet: Polyenes (see Lestner et al
British J Clin Pharmacology)
Fact Sheet: Echinocandins (see Lestner
et al British J Clin Pharmacology)
• Caspofungin 70 mg/m2 then 50 mg/m2
• Micafungin 2 mg/kg
• Anidulafungin 0.75-1.5 mg/kg/day
Pharmacokinetic Variability
Variability
• Essentially two types of variability
– Explained (covariates like weight, gender,
ethnicity, pharmacogenetics etc. etc.)
– Unexplained (residual)
• Physicians (in general) generally place too
much faith in covariates
• Children have variable PK, most of which we
don’t understand, and cannot predict!!
Variability is the Issue!
Consequences of Variability
• Lower drug exposure than intended
– Concentration-dependent therapeutic failure
– Generation of AMR
• Higher drug exposure than intended
– Toxicity
• Makes design of a fixed regimen really quite
difficult
– Trade toxicity and efficacy back and forwards
What can be done about
variability?
Stochastic Control
• Simply means control of system whose
properties (state) can only be estimated
– (i.e. a patient)
Information from past experiences
from many patients is “stored” in
population PK models
New Information from a patient
now allows a robust estimate of the
way a patient is handling a drug
Pharmacodynamic differences
• Much of PK-PD bridging makes an assumption
that the host is only marginally important
– The antifungal drug exerts its effect by docking with
the fungus inside the host
• The pathogenesis/ pathology of IFIs is
comparable between children and adults
– This argument used by regulators to prevent large
clinical studies in children
• But, there are times when there are
pharmacodynamic differences in pediatric
patients and adults
I’ve told this story many times before,
so will not go through the blow-byblow description
• In summary, neonates are at increased risk of
hematogenous Candida Meningoencephalitis
(HCME)
• Children and adults don’t (or rarely) get this
disease
• There are clearly pharmacodynamic differences
that require higher weight-based dosages of
antifungal agents such as…
– Micafungin
– Anidulafungin
Consequences of giving more drug
•
•
•
•
Just giving more drug is not necessarily trivial!
Issue of tox coverage in preclinical GLP studies
Issue of the safety of the excipient
One issue for anidulafungin is the use of
Tween 80, which itself has an upper safety
margin
• Area of ongoing debate between the EMA and
Pfizer about use of anidulafungin in neonates
Consequences
• Debate & tension that revolves around:
– The preclinical PK-PD model (are they right, are
they giving the right answer etc. etc., is the
science solid?)
• PK-PD investigators
– The risk and cost that is carried by the sponsor
– The societal and ethical requirement to develop
drugs for children
• Regulators
…and Regulatory Science ≠
Science Science
Over to Brian!