Transcript It is very difficult to assess the outcome and efficacy of

Issues in TB Drug
Development
For a Paediatric Indication
PR Donald
Paediatrics and Child Health
Tygerberg Children’s Hospital
Stellenbosch University
Cape Town
South Africa
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.”
Issues in TB Drug Development for
a Paediatric Indication
1.
2.
3.
4.
Importance of childhood tuberculosis
Features of childhood tuberculosis
Children are not just small adults
Examples of pharmacokinetic
differences between adults and children
5. Examples of approach in previous
evaluations of TB therapy in children
6. Conclusion
Importance of childhood
tuberculosis
• 5% of the tuberculosis case load in
developed communities
BUT
• Between 20-40% in developing
communities
Donald PR, Int J Tuberc Lung Dis 2004;8: 627-629)
Features of Childhood
Tuberculosis
• Mortality and morbidity is age related
The youngest children will often be
the sickest children
• Miliary tuberculosis
• Tuberculous meningitis
• Lymphobronchial tuberculosis
Features of Childhood
Tuberculosis
• Cavitation is uncommon, lesions are thus
usually paucibacillary
• Organisms are dormant or intermittently active
• Frequently culture negative (at best 40% culture
positive)
• Seldom smear-positive
• Radiological extent of disease is not necessarily
related to bacteriological burden
Features of Childhood
Tuberculosis
If evaluated shortly after infection:
• Gastric aspirate may yield a positive culture
• Culture of urine is reported positive in 20% or
more of children
• Chest radiograph may show adenopathy in up
to 80% of individuals
• Chest radiograph may be normal, but gastric
aspirate culture positive and CT or MRI shows
adenopathy !!
Mortality in relation to age
Age (yrs)
Number infected
0-1
39
1-3
64
3-7
225
7-16
125
Young adults
507
Mortality (%)
36.9
15.6
4.4
0.8
0.8
Wallgren A. Primary tuberculous infections in young
adult life and in childhood. Am J Dis Child 1941; 61:
577-589
Mortality in relation to age
Age of child
Mortality (%)
<6-months
55
1-2 years
28
4-9
15
Lincoln EM. Course and prognosis of
tuberculosis in children. Am J Med 1950: 9:
623-632
Mortality in relation to age
South Africa 1971-1980
Age (yrs)
Mortality (%)
<1
7.1
1-4
2.8
5-9
1.1
10-14
1.5
Küstner HGV, Tuberculosis in children.
Epidemiological Comments 1981; 8: 1-19
Children are not just small
adults!
Response to tuberculosis infection
• Differing spectrum of disease
• 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: increases by 2005% 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
Children are not just small
adults!
Developmental differences in all
aspects of drug metabolism
•
•
•
•
•
Absorption
Distribution
Excretion
Less toxicity (antituberculosis agents)
More toxicity (chloramphenicol)
(See McCarver DG. Pediatrics 2004; 113: 969972)
Mean peak serum concentrations (µg/ml) of
ethambutol in relation to dose in adults
Authors
Place&Thomas (1963)
Bobrowitz& Gokulnathan(1965)
Peets et al (1965)
Gómez-Pimienta et al (1966)
Donomae I, Yamamoto (1966)
Place et al (1966)
Horsfall (1969)
Eule & Werner (1970)
No
10
10
2
64
46
3
7
10
10
10
10
10
25
10
Dose (mg/kg)
50
25
17
25
15
25
20
25
12.5
4
8
12.5
25
50
25
25
Peak
10
5
2
4. 1
2.
5
3.
4.4
1.2
0.67
1.4
2.0
4.0
8.5
4.1
11
Mean peak serum concentrations (µg/ml) of
ethambutol in relation to dose in adults
Authors
Lee et al (1977)
Israili et al (1987)
1st day
Days 4-7
Kumar K (1992)
Schall et al (1995)
Peloquin et al (1999) (Fasting)
(Non-fast)
Zhu et al (2004)
Healthy volunteers
No
Dose (mg/kg)
6
17
17
10
50
75
15
12.5
12.5
25
20
14
14
38
18
16
7.5 
25 
25 
19
20
18 
Peak
8
4
4.01
3.7
5
8.2
6.4
1.45
4.5
3.8
2.11
2.06
3.21
Mean peak serum concentrations (µg/ml) of
ethambutol in relation to dose in children
Authors
Hussels & Otto (1971)
Hussels et al (1973
No
6
6
7
4
7
8
5
9
14
5
9
14
Dose (mg/kg)
Age (years)
Peak
15
15
15
25
25
25
2-5
6-9
10-14
2-5
6-9
10-14
1.2
1.1
0.9
2.0
1.5
2.8
35
35
35
35 
35 
35 
2-5
6-9
10-14
2-5
6-9
10-14
1.5
2.3
3.0
2.5
2.5
6.3
♥ given with rifampicin 10 mg/kg bodyweight given with rifampicin 10 mg/kg
bodyweight
Mean peak serum concentrations
(µg/ml) of ethambutol in relation to
dose in children
Authors
Benkert (1974
Zhu et al 2004
No
4
4
5
5
5
3
14
Dose (mg/kg)
15
15
15
25
25
25
Mean 16
Age (years)
3-6
7-10
11-14
3-6
7-10
11-14
Mean 5.4
Peak
0.9
2.0
1.8
3.0
2.6
3.5
0.78
The data used in figure are derived from papers listed in tables 2 and 3.
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
Schaaf HS et al. Isoniazid pharmacokinetics in children
treated for respiratory tuberculosis. Arch Dis Child
2005;90:614-618
• 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
Schaaf HS et al. Isoniazid pharmacokinetics in children
treated for respiratory tuberculosis. Arch Dis Child
2005;90:614-618
• 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)
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
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
5
10
15
20
25
C
0
[rifampicin] mg/l
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)
Assessment of response to
antituberculosis agents
In adults:
• Sputum smear for AFB or
• Sputum culture for M tuberculosis
• Other features such as radiological
changes or weight gain are interesting,
but not necessarily associated with the all
important microbiological measures of
response to treatment
Assessment of response to
antituberculosis agents
Sputum culture can then be further refined:
• Early bactericidal activity (EBA)
• Serial colony counting (SCC)
• Time to culture negativity
• Relapse rates
• Emergence of resistance
Assessment of response to
antituberculosis agents
In children:
• Seldom microscopy smear-positive
• Often culture negative
• Tendency, especially in older children, for
‘spontaneous’ recovery
• Hilar adenopathy may remain present for
up to 2 years and may increase in size
despite successful treatment
• Seth V. Antituberculous therapy in children.
Indian J Pediatr 1986; 53: 179-198.
• Radiological improvement is used as an
objective criterion of success.
• Graded as: I. Complete clearance
II. Moderate to significant clearance
III. Mild clearance
IV. No clearance or deterioration
Abernathy RS, Dutt AK, Stead WW, Moers DJ.
Short-course chemotherapy for tuberculosis in
children. Pediatrics 1983; 72: 801-806.
The response to treatment was judged by:
• Elimination of symptoms
• Negative sputum cultures. Cultures
became negative within 3- months in all 5
patients with positive cultures to start
with.
• Disappearance of extra-pulmonary
findings
Abernathy RS, Dutt AK, Stead WW, Moers DJ.
Short-course chemotherapy for tuberculosis in
children. Pediatrics 1983; 72: 801-806.
• Clearing of chest radiograph findings.
Lymphadenopathy resolved slowly. In 12
children (50% of those with nodes) nodes
did not clear for 2-3 years. Of 23 patients
with pulmonary infiltrates 4 (17%) had
residual infiltrates after 9 months of
treatment.
Varudkar BL. Short course chemotherapy in
children. Indian J Pediatr 1985; 52: 593-597.
Response was judged by:
• Symptomatic relief
• Good weight gain
• Disappearance of radiological lesions
Kumar L, Dhand R, Singhi PD, Rao LN, Katariy
S. A randomized trial of fully intermittent vs.
daily followed by intermittent short course
chemotherapy for childhood tuberculosis.
Pediatr Infect Dis J 1990; 9: 802-806.
Criteria used to assess response to
treatment pulmonary tuberculosis:
• General improvement; normalization of
temperature, improvement in appetite and
weight gain
Kumar L, Dhand R, Singhi PD, Rao LN, Katariy S. A
randomized trial of fully intermittent vs. daily followed by
intermittent short course chemotherapy for childhood
tuberculosis. Pediatr Infect Dis J 1990; 9: 802-806
• The radiological response and this was graded as:
Marked if the lesions cleared within 3-months and
no new lesions appeared,
Moderate if there was partial clearance of the
radiological lesions within 3-months and no fresh
lesions or
Poor if there was no radiological clearance or an
increase in the size of pulmonary lesions or the
appearance of new lesions.
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
• All children had radiological improvement after 6months of treatment, but chest radiographs were
completely normal in only 21 (22%). Mediastinal
nodes persisted until the end of treatment in 31
children (32%) and residual parenchymal changes
were present in 12 patients (24% of those who
presented with such lesions)
Te Water Naude J, Donald PR, Hussey GD, Kibel MA,
Louw A, Perkins DR, Schaaf HS. Twice weekly vs.
daily chemotherapy for childhood tuberculosis.
Pediatr Infect Dis J 2000; 19: 405-410.
Assessment of treatment response made use of:
• Parents assessment: worse, not better, better or much
better
• Clinical symptoms: worse, unchanged, better, much
better
• Weight gain: lost weight, unchanged, gained weight,
significant gain
• Chest radiograph: worse, unchanged, some clearing,
definite clearing
Al-Dossary FS, Ong LT, Correa AG, Starke JR.
Treatment of childhood tuberculosis with a six
month directly observed regimen of only two
weeks of daily therapy. Pediatr Infect Dis J 2002;
21: 91-97
Assessment of response to treatment:
• Improvement in symptoms (if present initially)
• Weight gain
• Improvement on examination in particular with
regard to lymph nodes
• Chest radiograph
Al-Dossary FS, Ong LT, Correa AG, Starke JR.
Treatment of childhood tuberculosis with a six
month directly observed regimen of only two
weeks of daily therapy. Pediatr Infect Dis J 2002;
21: 91-97
• In only 29% of cases were all clinical and
radiographic findings normal at the completion
of therapy
• In 66% of cases the CR was improved , but not
normal
• In 6% there was minimal or no improvement. In
all cases, however, good weight gain was noted
and all clinical symptoms had resolved. Only
one child relapsed and later admitted to noncompliance.
Swaminathan S, Raghavan A, Duraipandian M,
Kripasankar AS, Ramachandran P. Short-course
chemotherapy for paediatric respiratory
tuberculosis: 5-year report. Int J Tuberc Lung
Dis 2005; 9: 693-696.
At the end of treatment mediastinal nodes were
still seen in 23 (39%) of children who had
adenopathy at the start of treatment, but by 60
months all but one had resolved.
At the end of year 1 55% of chest radiographs
were normal and 71% at the end of 2 years; at
60 months after starting treatment 8% of
radiographs were still abnormal
How then best to
assess an
antituberculosis
agent for a
paediatric indication
?
How then best to assess an
antituberculosis agent for a
paediatric indication ?
Microbiology
• but children are frequently culture
negative
How then best to assess an
antituberculosis agent for a
paediatric indication ?
Radiology
• but often the radiological extent of disease bears no
relationship to the microbiological burden
• Radiological changes will frequently undergo spontaneous
remission
• Or the changes may remain present for several years
irrespective of the microbiological success of treatment
• In early pre-chemotherapy studies extent of disease on chest
radiograph was related to morbidity and mortality
How then best to assess an
antituberculosis agent for a
paediatric indication?
Utilise clinical features and radiology:
• Be careful about what is being assessed
• Hilar adenopathy alone does not have the same implications
as extensive lobar opacification
• Classify extent of disease on radiological grounds
• Radiological improvement, deterioration
• Relapse, recurrence, regression
• Microbiology when positive
• General ’well-being’ especially weight
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 dos