Issues in TB Drug Development For a Paediatric Indication PR Donald PR Donald Paediatrics and Child Health Tygerberg Children’s Hospital Stellenbosch University

Issues in TB Drug Issues in TB Drug Development Development

For a Paediatric IndicationFor a Paediatric Indication

PR DonaldPR Donald Paediatrics and Child HealthPaediatrics and Child Health

Tygerberg Children’s HospitalTygerberg Children’s Hospital Stellenbosch UniversityStellenbosch University

Cape TownCape TownSouth AfricaSouth Africa

Reis FJC, Bedran MBM, Moura JAR, Assis I, Rodrigues Reis FJC, Bedran MBM, Moura JAR, Assis I, Rodrigues MESM. Six-month isoniazid-rifampin treatment for MESM. Six-month isoniazid-rifampin treatment for

pulmonary tuberculosis in children. Am Rev Respir Dis pulmonary tuberculosis in children. Am Rev Respir Dis 1990; 142: 996-9991990; 142: 996-999

• ““It is very difficult to assess the outcome It is very difficult to assess the outcome and efficacy of any regimen for treatment and efficacy of any regimen for treatment of tuberculosis in children because they of tuberculosis in children because they rarely have positive sputum and gastric rarely have positive sputum and gastric washings and the best criteria would be washings and the best criteria would be clinical findings, such as weight gain and clinical findings, such as weight gain and radiologic follow-up studies.” radiologic follow-up studies.”

Issues in TB Drug Development for Issues in TB Drug Development for a Paediatric Indicationa Paediatric Indication

1.1. Importance of childhood tuberculosisImportance of childhood tuberculosis2.2. Features of childhood tuberculosisFeatures of childhood tuberculosis3.3. Children are not just small adultsChildren are not just small adults4.4. Examples of pharmacokinetic Examples of pharmacokinetic

differences between adults and childrendifferences between adults and children5.5. Examples of approach in previous Examples of approach in previous

evaluations of TB therapy in childrenevaluations of TB therapy in children6.6. ConclusionConclusion

Importance of childhood Importance of childhood tuberculosistuberculosis

• 5% of the tuberculosis case load in 5% of the tuberculosis case load in developed communitiesdeveloped communities

BUTBUT• Between 20-40% in developing Between 20-40% in developing

communitiescommunities

Donald PR, Int J Tuberc Lung Dis 2004;8: 627-629)

Features of Childhood Features of Childhood TuberculosisTuberculosis

• Mortality and morbidity is age relatedMortality and morbidity is age related

The youngest children will often beThe youngest children will often bethe sickest childrenthe sickest children

• Miliary tuberculosisMiliary tuberculosis• Tuberculous meningitisTuberculous meningitis• Lymphobronchial tuberculosis Lymphobronchial tuberculosis


• Cavitation is uncommon, lesions are thus Cavitation is uncommon, lesions are thus usually paucibacillaryusually paucibacillary

• Organisms are dormant or intermittently activeOrganisms are dormant or intermittently active• Frequently culture negative (at best 40% culture Frequently culture negative (at best 40% culture

positive)positive)• Seldom smear-positiveSeldom smear-positive• Radiological extent of disease is not necessarily Radiological extent of disease is not necessarily

related to bacteriological burdenrelated to bacteriological burden


If evaluated shortly after infection:If evaluated shortly after infection:• Gastric aspirate may yield a positive cultureGastric aspirate may yield a positive culture• Culture of urine is reported positive in 20% or Culture of urine is reported positive in 20% or

more of childrenmore of children• Chest radiograph may show adenopathy in up to Chest radiograph may show adenopathy in up to

80% of individuals80% of individuals• Chest radiograph may be normal, but gastric Chest radiograph may be normal, but gastric

aspirate culture positive and CT or MRI shows aspirate culture positive and CT or MRI shows adenopathy !!adenopathy !!

Mortality in relation to ageMortality in relation to age

Age (yrs)Age (yrs) Number infectedNumber infected Mortality (%)Mortality (%)0-10-1 3939 36.936.91-31-3 6464 15.615.63-73-7 225225 4.44.47-167-16 125125 0.80.8Young adultsYoung adults 507507 0.80.8

Wallgren A. Primary tuberculous infections in young adult Wallgren A. Primary tuberculous infections in young adult life and in childhood. Am J Dis Child 1941; 61: 577-589life and in childhood. Am J Dis Child 1941; 61: 577-589

Mortality in relation to ageMortality in relation to age

Age of child Age of child Mortality (%)Mortality (%)<6-months<6-months 55551-2 years1-2 years 28284-9 4-9 1515

Lincoln EM. Course and prognosis of Lincoln EM. Course and prognosis of tuberculosis in children. Am J Med 1950: 9: tuberculosis in children. Am J Med 1950: 9:

623-632623-632

Mortality in relation to ageMortality in relation to ageSouth Africa 1971-1980South Africa 1971-1980

Age (yrs)Age (yrs) Mortality (%)Mortality (%)<1<1 7.17.1

1-41-4 2.82.85-95-9 1.11.1

10-1410-14 1.51.5Küstner HGV, Tuberculosis in children. Küstner HGV, Tuberculosis in children.

Epidemiological Comments 1981; 8: 1-19 Epidemiological Comments 1981; 8: 1-19

Children are not just small Children are not just small adults!adults!

Response to tuberculosis infectionResponse to tuberculosis infection• Differing spectrum of diseaseDiffering spectrum of disease• Disease vs InfectionDisease vs Infection• Relatively benign course of most Relatively benign course of most

tuberculosis infectionstuberculosis infections


Non-linear changes in body compositionNon-linear changes in body composition• Body weight: Doubles by 5-months, triples by a year.Body weight: Doubles by 5-months, triples by a year.• Body length: increases by 50% by 1-yearBody length: increases by 50% by 1-year• Body surface area: increases by 2005% by 1-yearBody surface area: increases by 2005% by 1-year• Total body water:Total body water: 85% in premature neonate85% in premature neonate 70% in full term infant70% in full term infant 55% in an adult55% in an adult• Protein binding reaches adult levels at approximately 1-Protein binding reaches adult levels at approximately 1-

yearyear


Developmental differences in all Developmental differences in all aspects aspects of drug metabolismof drug metabolism

• AbsorptionAbsorption• DistributionDistribution• ExcretionExcretion• Less toxicity (antituberculosis agents)Less toxicity (antituberculosis agents)• More toxicity (chloramphenicol)More toxicity (chloramphenicol)

(See McCarver DG. Pediatrics 2004; 113: 969-972)(See McCarver DG. Pediatrics 2004; 113: 969-972)

Mean peak serum concentrations (µg/ml) of Mean peak serum concentrations (µg/ml) of ethambutol in relation to dose in adultsethambutol in relation to dose in adults

AuthorsAuthors NoNo Dose (mg/kg)Dose (mg/kg) PeakPeakPlace&Thomas (1963)Place&Thomas (1963) 1010 5050 1010

1010 2525 5522 1717 22

Bobrowitz& Gokulnathan(1965)Bobrowitz& Gokulnathan(1965) 6464 2525 4. 14. 14646 1515 2.2.

Peets et al (1965)Peets et al (1965) 33 2525 55Gómez-Pimienta et al (1966)Gómez-Pimienta et al (1966) 77 2020 3.3.Donomae I, Yamamoto (1966)Donomae I, Yamamoto (1966) 2525 4.44.4

12.512.5 1.21.2Place et al (1966)Place et al (1966) 1010 44 0.670.67

1010 88 1.41.41010 12.512.5 2.02.01010 2525 4.04.01010 5050 8.58.5

Horsfall (1969)Horsfall (1969) 2525 2525 4.14.1Eule & Werner (1970)Eule & Werner (1970) 1010 2525 1111

Mean peak serum concentrations (µg/ml) of Mean peak serum concentrations (µg/ml) of ethambutol in relation to dose in adultsethambutol in relation to dose in adults

AuthorsAuthors NoNoDose (mg/kg)Dose (mg/kg)PeakPeak5050 887575 44

Lee et al (1977)Lee et al (1977) 661515 4.014.01Israili et al (1987)Israili et al (1987) 11stst day day 171712.512.5 3.73.7

Days 4-7Days 4-7 1717 12.512.555Kumar K (1992)Kumar K (1992) 10102525 8.28.2

6.46.4Schall et al (1995)Schall et al (1995) 20207.5 7.5 1.451.45Peloquin et al (1999)Peloquin et al (1999) (Fasting)(Fasting) 141425 25 4.54.5

(Non-fast)(Non-fast) 1414 25 25 3.83.8Zhu et al (2004)Zhu et al (2004) 38381919 2.112.11

1818 2020 2.062.061616 18 18 3.213.21

Healthy volunteersHealthy volunteers

Mean peak serum concentrations (µg/ml) of Mean peak serum concentrations (µg/ml) of ethambutol in relation to dose in childrenethambutol in relation to dose in children

AuthorsAuthors NoNoDose (mg/kg)Dose (mg/kg) Age (years)Age (years) PeakPeakHussels & Otto (1971)Hussels & Otto (1971) 661515 2-52-5 1.21.2

66 1515 6-96-9 1.11.177 1515 10-1410-14 0.90.944 2525 2-52-5 2.02.077 2525 6-96-9 1.51.588 2525 10-1410-14 2.82.8

Hussels et al (1973Hussels et al (1973 553535 2-52-5 1.51.599 3535 6-96-9 2.32.31414 3535 10-1410-14 3.03.055 35 35 2-52-5 2.52.599 3535 6-96-9 2.52.51414 3535 10-1410-14 6.36.3

♥ ♥ given with rifampicin 10 mg/kg bodyweight given with rifampicin 10 mg/kg given with rifampicin 10 mg/kg bodyweight given with rifampicin 10 mg/kg bodyweightbodyweight

Mean peak serum concentrations Mean peak serum concentrations (µg/ml) of ethambutol in relation to (µg/ml) of ethambutol in relation to

dose in childrendose in children

AuthorsAuthors No No Dose (mg/kg)Dose (mg/kg) Age (years)Age (years) PeakPeakBenkert (1974Benkert (1974 44 1515 3-63-6 0.90.9

44 1515 7-107-10 2.02.055 1515 11-1411-14 1.81.855 2525 3-63-6 3.03.055 2525 7-107-10 2.62.633 2525 11-1411-14 3.53.5

Zhu et al 2004Zhu et al 2004 1414 Mean 16Mean 16 Mean 5.4Mean 5.4 0.780.78

The data used in figure are derived from papers listed in tables 2 and 3. 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 two lines are Adults: y=0.1602*Dose and Children: y=0.0906*Dose.

The standard errors of the two slope coefficients are respectively, The standard errors of the two slope coefficients are respectively, 0.005833 and 0.009080. The difference between the slopes is clearly 0.005833 and 0.009080. The difference between the slopes is clearly

significantsignificant

Schaaf HS et al. Isoniazid pharmacokinetics in children Schaaf HS et al. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Arch Dis Child treated for respiratory tuberculosis. Arch Dis Child

2005;90:614-6182005;90:614-618

• INH serum concentrations determined at INH serum concentrations determined at 2-, 3-, 4- and 5-hours after dosing with 2-, 3-, 4- and 5-hours after dosing with INH 10 mg/kg bodyweight in 64 children INH 10 mg/kg bodyweight in 64 children median age 3.8 yearsmedian age 3.8 years

Schaaf HS et al. Isoniazid pharmacokinetics in children Schaaf HS et al. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Arch Dis Child treated for respiratory tuberculosis. Arch Dis Child

2005;90:614-6182005;90:614-618

• Compared to serum concentrations Compared to serum concentrations of INH in 60 adult patients also of INH in 60 adult patients also receiving 10 mg/kg bodyweight INH. receiving 10 mg/kg bodyweight INH. (Parkin et al Am J Respir Crit Care (Parkin et al Am J Respir Crit Care Med 1997; 155: 1717-1722)Med 1997; 155: 1717-1722)

1050

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Age

k

Slow: k vs AgeFitted line: k=0.268-0.00521*Age

1050

14

12

10

8

6

4

2

0

Age

2hr

IN

H c

onc

.

Slow(SS) : 2hr INH concentration vs AgeConc = 7.283+0.278 Age

AUC and 2-hour serum concentrations AUC and 2-hour serum concentrations of INH in adults and children after an of INH in adults and children after an

INH dose of 10 mg/kg body weightINH dose of 10 mg/kg body weight

GenotypeGenotype AUC (mg/l/hr)AUC (mg/l/hr) 2 hr Conc2 hr Conc (µg/ml) (µg/ml) AdultsAdults ChildChild AdultsAdults ChildChild

SSSS 24.924.9 18.3618.36 10.9410.94 8.608.60FSFS 15.3815.38 8.258.25 8.708.70 5.135.13FFFF 8.148.14 5.375.37 6.036.03 3.943.94

0

2

4

6

8

10

12

14

1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0time

A

A Error

C

C Error

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

05

1015

2025

A C

[rifa

mpi

cin]

mg/

l

Graphs by adult_child

Peak rifampicin serum concentrations in adults Peak rifampicin serum concentrations in adults (A) and children (C). (Kruskall-Wallis P=0.562(A) and children (C). (Kruskall-Wallis P=0.562)

020

4060

8010

0

A C

rifam

pici

n A

UC

(0-6

hr) m

g.h/

l


Rifampicin area under the curve (AUC) in adults (A) and children (C). (Kruskall-Wallis P=0.009)

02

46

8

A C

rifam

pici

n ha

lf lif

e (h

)


Rifampicin half-life in adults (A) and children (C). Rifampicin half-life in adults (A) and children (C). (Kruskall-Wallis P=0.0001(Kruskall-Wallis P=0.0001)

Assessment of response to Assessment of response to antituberculosis agentsantituberculosis agents

In adults:In adults:• Sputum smear for AFB orSputum smear for AFB or• Sputum culture for Sputum culture for M tuberculosisM tuberculosis• Other features such as radiological Other features such as radiological

changes or weight gain are interesting, changes or weight gain are interesting, but not necessarily associated with the all but not necessarily associated with the all important microbiological measures of important microbiological measures of response to treatmentresponse to treatment


Sputum culture can then be further refined:Sputum culture can then be further refined:• Early bactericidal activity (EBA)Early bactericidal activity (EBA)• Serial colony counting (SCC)Serial colony counting (SCC)• Time to culture negativityTime to culture negativity• Relapse ratesRelapse rates• Emergence of resistanceEmergence of resistance


In children:In children:• Seldom microscopy smear-positiveSeldom microscopy smear-positive• Often culture negativeOften culture negative• Tendency, especially in older children, for Tendency, especially in older children, for

‘spontaneous’ recovery‘spontaneous’ recovery• Hilar adenopathy may remain present for Hilar adenopathy may remain present for

up to 2 years and may increase in size up to 2 years and may increase in size despite successful treatmentdespite successful treatment

• Seth V. Antituberculous therapy in children. Indian Seth V. Antituberculous therapy in children. Indian J Pediatr 1986; 53: 179-198.J Pediatr 1986; 53: 179-198.

• Radiological improvement is used as an objective Radiological improvement is used as an objective criterion of success.criterion of success.

• Graded as:Graded as: I.I.Complete clearanceComplete clearanceII.II.Moderate to significant clearanceModerate to significant clearanceIII.III.Mild clearanceMild clearanceIV.IV.No clearance or deteriorationNo clearance or deterioration

Abernathy RS, Dutt AK, Stead WW, Moers DJ. Abernathy RS, Dutt AK, Stead WW, Moers DJ. Short-course chemotherapy for tuberculosis in Short-course chemotherapy for tuberculosis in children. Pediatrics 1983; 72: 801-806.children. Pediatrics 1983; 72: 801-806.

The response to treatment was judged by:The response to treatment was judged by:• Elimination of symptomsElimination of symptoms• Negative sputum cultures. Cultures Negative sputum cultures. Cultures

became negative within 3- months in all 5 became negative within 3- months in all 5 patients with positive cultures to start patients with positive cultures to start with.with.

• Disappearance of extra-pulmonary Disappearance of extra-pulmonary findingsfindings

Abernathy RS, Dutt AK, Stead WW, Moers DJ. Abernathy RS, Dutt AK, Stead WW, Moers DJ. Short-course chemotherapy for tuberculosis in Short-course chemotherapy for tuberculosis in children. Pediatrics 1983; 72: 801-806.children. Pediatrics 1983; 72: 801-806.

• Clearing of chest radiograph findings. Clearing of chest radiograph findings. Lymphadenopathy resolved slowly. In 12 Lymphadenopathy resolved slowly. In 12 children (50% of those with nodes) nodes children (50% of those with nodes) nodes did not clear for 2-3 years. Of 23 patients did not clear for 2-3 years. Of 23 patients with pulmonary infiltrates 4 (17%) had with pulmonary infiltrates 4 (17%) had residual infiltrates after 9 months of residual infiltrates after 9 months of treatment.treatment.

Varudkar BL. Short course chemotherapy in Varudkar BL. Short course chemotherapy in children. Indian J Pediatr 1985; 52: 593-597.children. Indian J Pediatr 1985; 52: 593-597.

Response was judged by: Response was judged by:

• Symptomatic reliefSymptomatic relief• Good weight gainGood weight gain• Disappearance of radiological lesionsDisappearance of radiological lesions

Kumar L, Dhand R, Singhi PD, Rao LN, Katariy Kumar L, Dhand R, Singhi PD, Rao LN, Katariy S. A randomized trial of fully intermittent S. A randomized trial of fully intermittent vs.vs. daily followed by intermittent short course daily followed by intermittent short course chemotherapy for childhood tuberculosis. chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990; 9: 802-806.Pediatr Infect Dis J 1990; 9: 802-806.

Criteria used to assess response to Criteria used to assess response to treatment pulmonary tuberculosis:treatment pulmonary tuberculosis:

• General improvement; normalization of General improvement; normalization of temperature, improvement in appetite and temperature, improvement in appetite and weight gainweight gain

Kumar L, Dhand R, Singhi PD, Rao LN, Katariy S. A Kumar L, Dhand R, Singhi PD, Rao LN, Katariy S. A randomized trial of fully intermittent randomized trial of fully intermittent vs.vs. daily followed by daily followed by

intermittent short course chemotherapy for childhood intermittent short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990; 9: 802-806tuberculosis. Pediatr Infect Dis J 1990; 9: 802-806

• The radiological response and this was graded as: The radiological response and this was graded as:

MarkedMarked if the lesions cleared within 3-months and if the lesions cleared within 3-months and no new lesions appeared,no new lesions appeared,

Moderate Moderate if there was partial clearance of the if there was partial clearance of the radiological lesions within 3-months and no fresh radiological lesions within 3-months and no fresh lesions orlesions or

PoorPoor if there was no radiological clearance or an if there was no radiological clearance or an increase in the size of pulmonary lesions or the increase in the size of pulmonary lesions or the appearance of new lesions. appearance of new lesions.

Reis FJC, Bedran MBM, Moura JAR, Assis I, Reis FJC, Bedran MBM, Moura JAR, Assis I, Rodrigues MESM. Six-month isoniazid-rifampin Rodrigues MESM. Six-month isoniazid-rifampin

treatment for pulmonary tuberculosis in treatment for pulmonary tuberculosis in children. Am Rev Respir Dis 1990; 142: 996-999children. Am Rev Respir Dis 1990; 142: 996-999

• All children had radiological improvement after 6-All children had radiological improvement after 6-months of treatment, but chest radiographs were months of treatment, but chest radiographs were completely normal in only 21 (22%). Mediastinal completely normal in only 21 (22%). Mediastinal nodes persisted until the end of treatment in 31 nodes persisted until the end of treatment in 31 children (32%) and residual parenchymal changes children (32%) and residual parenchymal changes were present in 12 patients (24% of those who were present in 12 patients (24% of those who presented with such lesions)presented with such lesions)

Te Water Naude J, Donald PR, Hussey GD, Kibel MA, Te Water Naude J, Donald PR, Hussey GD, Kibel MA, Louw A, Perkins DR, Schaaf HS. Twice weekly Louw A, Perkins DR, Schaaf HS. Twice weekly vs.vs. daily chemotherapy for childhood tuberculosis. daily chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 2000; 19: 405-410.Pediatr Infect Dis J 2000; 19: 405-410.

Assessment of treatment response made use of:Assessment of treatment response made use of:

• Parents assessment: worse, not better, better or much Parents assessment: worse, not better, better or much betterbetter

• Clinical symptoms: worse, unchanged, better, much Clinical symptoms: worse, unchanged, better, much betterbetter

• Weight gain: lost weight, unchanged, gained weight, Weight gain: lost weight, unchanged, gained weight, significant gainsignificant gain

• Chest radiograph: worse, unchanged, some clearing, Chest radiograph: worse, unchanged, some clearing, definite clearingdefinite clearing

Al-Dossary FS, Ong LT, Correa AG, Starke JR. Al-Dossary FS, Ong LT, Correa AG, Starke JR. Treatment of childhood tuberculosis with a six Treatment of childhood tuberculosis with a six month directly observed regimen of only two month directly observed regimen of only two weeks of daily therapy. Pediatr Infect Dis J 2002; weeks of daily therapy. Pediatr Infect Dis J 2002; 21: 91-9721: 91-97

Assessment of response to treatment:Assessment of response to treatment:

• Improvement in symptoms (if present initially) Improvement in symptoms (if present initially) • Weight gainWeight gain• Improvement on examination in particular with Improvement on examination in particular with

regard to lymph nodesregard to lymph nodes• Chest radiograph Chest radiograph

Al-Dossary FS, Ong LT, Correa AG, Starke JR. Al-Dossary FS, Ong LT, Correa AG, Starke JR. Treatment of childhood tuberculosis with a six Treatment of childhood tuberculosis with a six month directly observed regimen of only two month directly observed regimen of only two weeks of daily therapy. Pediatr Infect Dis J 2002; weeks of daily therapy. Pediatr Infect Dis J 2002; 21: 91-9721: 91-97

• In only 29% of cases were all clinical and In only 29% of cases were all clinical and radiographic findings normal at the completion radiographic findings normal at the completion of therapy of therapy

• In 66% of cases the CR was improved , but not In 66% of cases the CR was improved , but not normal normal

• In 6% there was minimal or no improvement. In In 6% there was minimal or no improvement. In all cases, however, good weight gain was noted all cases, however, good weight gain was noted and all clinical symptoms had resolved. Only and all clinical symptoms had resolved. Only one child relapsed and later admitted to non-one child relapsed and later admitted to non-compliance. compliance.

Swaminathan S, Raghavan A, Duraipandian M, Swaminathan S, Raghavan A, Duraipandian M, Kripasankar AS, Ramachandran P. Short-Kripasankar AS, Ramachandran P. Short-course chemotherapy for paediatric respiratory course chemotherapy for paediatric respiratory tuberculosis: 5-year report. Int J Tuberc Lung tuberculosis: 5-year report. Int J Tuberc Lung Dis 2005; 9: 693-696.Dis 2005; 9: 693-696.

At the end of treatment mediastinal nodes were At the end of treatment mediastinal nodes were still seen in 23 (39%) of children who had still seen in 23 (39%) of children who had adenopathy at the start of treatment, but by 60 adenopathy at the start of treatment, but by 60 months all but one had resolved.months all but one had resolved.

At the end of year 1 55% of chest radiographs At the end of year 1 55% of chest radiographs were normal and 71% at the end of 2 years; at were normal and 71% at the end of 2 years; at 60 months after starting treatment 8% of 60 months after starting treatment 8% of radiographs were still abnormal radiographs were still abnormal

How then best to How then best to assess an assess an

antituberculosis antituberculosis agent for a agent for a

paediatric indicationpaediatric indication

??

How then best to assess an How then best to assess an antituberculosis agent for a antituberculosis agent for a

paediatric indication ? paediatric indication ?

MicrobiologyMicrobiology• but children are frequently culture but children are frequently culture

negativenegative


paediatric indication ? paediatric indication ?

RadiologyRadiology• but often the radiological extent of disease bears no but often the radiological extent of disease bears no

relationship to the microbiological burdenrelationship to the microbiological burden• Radiological changes will frequently undergo spontaneous Radiological changes will frequently undergo spontaneous

remissionremission• Or the changes may remain present for several years Or the changes may remain present for several years

irrespective of the microbiological success of treatmentirrespective of the microbiological success of treatment• In early pre-chemotherapy studies extent of disease on chest In early pre-chemotherapy studies extent of disease on chest

radiograph was related to morbidity and mortalityradiograph was related to morbidity and mortality


paediatric indication?paediatric indication?Utilise clinical features and radiology:Utilise clinical features and radiology:

• Be careful about what is being assessedBe careful about what is being assessed• Hilar adenopathy alone does not have the same Hilar adenopathy alone does not have the same

implications as extensive lobar opacificationimplications as extensive lobar opacification• Classify extent of disease on radiological groundsClassify extent of disease on radiological grounds• Radiological improvement, deteriorationRadiological improvement, deterioration• Relapse, recurrence, regressionRelapse, recurrence, regression• Microbiology when positiveMicrobiology when positive• General ’well-being’ especially weightGeneral ’well-being’ especially weight


paediatric indication? paediatric indication?

Perhaps? Perhaps?

• Accept evidence of efficacy from adult studiesAccept evidence of efficacy from adult studiesBUTBUT

• Evaluate differences in pharmacokinetics and Evaluate differences in pharmacokinetics and pharmacodynamics before making a pharmacodynamics before making a recommendation for dos recommendation for dos

Documents

Issues in TB Drug Development For a Paediatric Indication PR Donald PR Donald Paediatrics and Child Health Tygerberg Children’s Hospital Stellenbosch University