Download Children are not just small adults!

Doses of anti-TB drugs for children:
promoting the development of
improved recommendations based on
pharmacokinetic studies in children
HS Schaaf, PR Donald
Paediatrics and Child Health
Tygerberg Children’s Hospital
Stellenbosch University
Cape Town
South Africa
“It is very difficult to assess the outcome
and efficacy of any regimen for treatment
of tuberculosis in children because they
rarely have positive sputum and gastric
washings and the best criteria would be
clinical findings, such as weight gain and
radiologic follow-up studies.”
Reis FJC, Bedran MBM, Moura JAR, Assis I, Rodrigues
MESM. Six-month isoniazid-rifampin treatment for
pulmonary tuberculosis in children. Am Rev Respir Dis
1990; 142: 996-999
Children are not just small adults!
Response to tuberculosis infection
• Differing spectrum of disease (EPTB)
• Disease vs. Infection
• Relatively benign course of most
tuberculosis infections
Children are not just small adults!
Non-linear changes in body composition
•
•
•
•
•
Body weight: doubles by 5-months, triples by a year.
Body length: increases by 50% by 1-year
Body surface area: doubles by 1-year
Total body water: 85% in premature neonate
70% in full term infant
55% in an adult
Protein binding reaches adult levels at approximately 1year
• Similar to adults, a relationship between
what the body does with a drug
(pharmacokinetics) and what the drug
does to the body (pharmacodynamics) is
present in children
• It is mainly the pharmacokinetics that
change during childhood, but
pharmacodynamics is important, as some
drug adverse events may mainly present
in children
Children are not just small adults!
Developmental differences occur in all aspects of
drug metabolism
• Absorption (gastric pH, gastric emptying, first-pass
metabolism in stomach, bowel or liver)
• Distribution (changes in body composition, protein or
tissue binding)
• Metabolism (complicated, many enzymes involved)
• Excretion (liver and kidney are several fold greater relative
to body weight in children compared to adults)
(McCarver DG. Pediatrics 2004; 113: 969-972)
Anti-TB drug levels in children
• WHO recently published a literature
review on EMB by Peter Donald. This
showed:
“Peak serum EMB concentrations in both
children and adults increase in relation to
dose, but are significantly lower in
children than adults receiving the same
mg/kg body weight dose.”
It was recommended that the dose for
children should be 20 mg/kg (15-25 mg/kg)
The data used in figure are derived from a number of papers.
The two lines are Adults: y=0.1602*Dose and Children: y=0.0906*Dose. The
standard errors of the two slope coefficients are respectively, 0.005833
and 0.009080. The difference between the slopes is clearly significant
• INH serum concentrations determined at
2-, 3-, 4- and 5-hours after dosing with
INH 10 mg/kg bodyweight in 64 children
median age 3.8 years was • compared to serum concentrations of
INH in 60 adult patients also receiving 10
mg/kg bodyweight INH. (Parkin et al Am J
Respir Crit Care Med 1997; 155: 1717-1722)
Schaaf HS et al. Isoniazid pharmacokinetics in children
treated for respiratory tuberculosis. (Arch Dis Child
2005;90:614-618
Slow: k vs Age
Fitted line: k=0.268-0.00521*Age
1.0
0.9
0.8
0.7
k
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
5
10
Age
Slow(SS) : 2hr INH concentration vs Age
Conc = 7.283+0.278 Age
14
2hr INH conc.
12
10
8
6
4
2
0
0
5
10
Age
AUC and 2-hour serum concentrations
of INH in adults and children after an
INH dose of 10 mg/kg body weight
Genotype
SS
FS
FF
AUC (mg/l/hr)
Adults Child
24.9
18.36
15.38
8.25
8.14
5.37
2 hr Conc
Adults
10.94
8.70
6.03
(µg/ml)
Child
8.60
5.13
3.94
2-hr INH concentration vs. dose. The 2-hour INH serum
concentration associated with the EBA90 is 2.19 µg/ml
INH study results
• Considerable differences in exposure to
INH between slow, intermediate and fast
acetylators – in adults and children
• Younger children eliminate INH faster than
older children. In a trimodal model of INH
elimination there is a significant age
related decline in the first order
elimination rate constant (k, h-1) with age
in all three groups
INH study results
• Exposure of children to INH, as reflected by k h-1,
AUC (2-5 hrs after dosing) and INH concentration
at different time intervals after dosing, is
significantly less than that of a group of adults
drawn from the same population and receiving
the same mg/kg body weight dose of INH
• In this population, intermediate + fast acetylators
are in the majority (approx. 60%+)
INH study results
• These findings, taking into account the
NAT2 genotype, confirm that younger
children eliminate INH faster than older
children, and children, as a group, faster
than adults
• WHO and IUATLD currently recommend 5
mg/kg (4-6) INH for children and adults.
However, AAP recommends an INH dose
of 10-15 mg/kg/dose
14
12
10
8
A
A Error
6
C
C Error
4
2
0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
time
Median rifampicin concentrations in adults (red) and children
(pink) established on first-line treatment sampling 1.5, 3, 4 and 6
hours after dosing with standard daily doses
C
0
5
10
15
20
25
A
Graphs by adult_child
Peak rifampicin serum concentrations in adults
(A) and children (C). (Kruskall-Wallis P=0.562)
C
0
20
40
60
80
100
A
Graphs by adult_child
Rifampicin area under the curve (AUC) in adults (A)
and children (C). (Kruskall-Wallis P=0.009)
C
0
2
4
6
8
A
Graphs by adult_child
Rifampicin half-life in adults (A) and children (C).
(Kruskall-Wallis P=0.0001)
Rifampicin and Rifapentine
• Rifampicin results shown are provisional results
from a study in Cape Town (PR Donald, H
McIlleron, et al.)
• Pharmacokinetics of Rifapentine in children:
(MJ Blake et al. PIDJ 2006;25:405-408)
“Given a comparable weight-normalized dose,
rifapentine exposure estimates are lower in
children than those reported in adults,
suggesting that a larger weight-normalized (i.e.
mg/kg) dose of rifapentine is needed in
children”
Pyrazinamide
• Incomplete or delayed absorption was more
common in children than in adults
• Median volume of distribution (L/kg) was 32%
larger in children, and median clearance
(L/hr/kg) was 106% larger in children, with a
resultant median half-life 43% shorter in
children
M Zhu et al. Population pharmacokinetic modeling of
pyrazinamide in children and adults with tuberculosis.
Pharmacotherapy 2002;22:686-695
Pyrazinamide levels in children
Pyrazinamide
• Graham et al. found poor absorption of
PZA in Malawian children and that
younger children (<5 yrs) reached
significantly lower serum PZA
concentrations than older children
• In almost all cases , the Cmax failed to
reach the MIC for M. tuberculosis
How then best to assess an
antituberculosis agent for a
paediatric indication?
Perhaps?
• Accept evidence of efficacy from adult
studies
BUT
• Evaluate differences in pharmacokinetics and
pharmacodynamics before making a
recommendation for dose in children
“The true maximum dose is the highest
dose that a patient can tolerate, hopefully
while achieving the desired therapeutic
response”
Charles A Peloquin (1998)
Way Forward?
• Need more pharmacokinetic and
pharmacodynamic anti-TB agent studies
in children
• Reviews of existing data not only on EMB
and INH, but also on other first-line antiTB drugs (RMP, PZA)