Doses of anti-TB drugs for children: promoting the development of improved recommendations based on pharmacokinetic studies in children

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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 Childrens Hospital
• Stellenbosch University
• Cape Town
• South Africa

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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

• 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.

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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

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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 1-year

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• 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

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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)

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Anti-TB drug levels in children

• WHO recently published a literature review on EMB
  by Peter Donald. This showedPeak 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)

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The data used in figure are derived from a number
of papers. The two lines are Adults
y0.1602Dose and Children y0.0906Dose. The
standard errors of the two slope coefficients are
respectively, 0.005833 and 0.009080. The
difference between the slopes is clearly
significant
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Schaaf HS et al. Isoniazid pharmacokinetics in
children treated for respiratory tuberculosis.
(Arch Dis Child 200590614-618

• 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)

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AUC and 2-hour serum concentrations of INH in
adults and children after an INH dose of 10 mg/kg
body weight

• Genotype AUC (mg/l/hr) 2 hr Conc (µg/ml)
• Adults Child Adults Child
• SS 24.9 18.36 10.94 8.60
• FS 15.38 8.25 8.70 5.13
• FF 8.14 5.37 6.03 3.94

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2-hr INH concentration vs. dose. The 2-hour INH
serum concentration associated with the EBA90 is
2.19 µg/ml
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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

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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)

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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

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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
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Peak rifampicin serum concentrations in adults
(A) and children (C). (Kruskall-Wallis P0.562)
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Rifampicin area under the curve (AUC) in adults
(A) and children (C). (Kruskall-Wallis P0.009)
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Rifampicin half-life in adults (A) and children
(C). (Kruskall-Wallis P0.0001)
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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 200625405-408)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

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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 200222686-695

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Pyrazinamide levels in children
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Pyrazinamide

• Graham et al. found poor absorption of PZA in
  Malawian children and that younger children (lt5
  yrs) reached significantly lower serum PZA
  concentrations than older children
• In almost all cases , the Cmax failed to reach
  the MIC for M. tuberculosis

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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

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• The true maximum dose is the highest dose that a
  patient can tolerate, hopefully while achieving
  the desired therapeutic response
• Charles A Peloquin (1998)

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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 anti-TB drugs (RMP,
  PZA)