Issues in TB Drug Development For a Paediatric Indication

1. 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

2. 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.”

3. Issues in TB Drug Development for a Paediatric Indication • Importance of childhood tuberculosis • Features of childhood tuberculosis • Children are not just small adults • Examples of pharmacokinetic differences between adults and children • Examples of approach in previous evaluations of TB therapy in children • Conclusion

4. Importance of childhood tuberculosis • 5% of the tuberculosis case load in developed communities BUT • Between 20-40% in developing communities

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

7. 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

8. 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

22. 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 !!

23. Mortality in relation to age Age (yrs) Number infected Mortality (%) 0-1 39 36.9 1-3 64 15.6 3-7 225 4.4 7-16 125 0.8 Young adults 507 0.8 Wallgren A. Primary tuberculous infections in young adult life and in childhood. Am J Dis Child 1941; 61: 577-589

24. 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

25. Mortality in relation to ageSouth 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

26. Children are not just small adults! Response to tuberculosis infection • Differing spectrum of disease • Disease vs Infection • Relatively benign course of most tuberculosis infections

27. 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

28. 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: 969-972)

29. Mean peak serum concentrations (µg/ml) of ethambutol in relation to dose in adults Authors No Dose (mg/kg) Peak Place&Thomas (1963) 10 50 10 10 25 5 2 17 2 Bobrowitz& Gokulnathan(1965) 64 25 4. 1 46 15 2. Peets et al (1965) 3 25 5 Gómez-Pimienta et al (1966) 7 20 3. Donomae I, Yamamoto (1966) 25 4.4 12.5 1.2 Place et al (1966) 10 4 0.67 10 8 1.4 10 12.5 2.0 10 25 4.0 10 50 8.5 Horsfall (1969) 25 25 4.1 Eule & Werner (1970) 10 25 11

30. Mean peak serum concentrations (µg/ml) of ethambutol in relation to dose in adults Authors No Dose (mg/kg) Peak 50 8 75 4 Lee et al (1977) 6 15 4.01 Israili et al (1987) 1st day 17 12.5 3.7 Days 4-7 17 12.5 5 Kumar K (1992) 10 25 8.2 6.4 Schall et al (1995) 20 7.5  1.45 Peloquin et al (1999) (Fasting) 14 25  4.5 (Non-fast) 14 25  3.8 Zhu et al (2004) 38 19 2.11 18 20 2.06 16 18  3.21 Healthy volunteers

31. Mean peak serum concentrations (µg/ml) of ethambutol in relation to dose in children Authors No Dose (mg/kg) Age (years) Peak Hussels & Otto (1971) 6 15 2-5 1.2 6 15 6-9 1.1 7 15 10-14 0.9 4 25 2-5 2.0 7 25 6-9 1.5 8 25 10-14 2.8 Hussels et al (1973 5 35 2-5 1.5 9 35 6-9 2.3 14 35 10-14 3.0 5 35  2-5 2.5 9 35  6-9 2.5 14 35  10-14 6.3 ♥ given with rifampicin 10 mg/kg bodyweight given with rifampicin 10 mg/kg bodyweight

32. Mean peak serum concentrations (µg/ml) of ethambutol in relation to dose in children Authors No Dose (mg/kg) Age (years) Peak Benkert (1974 4 15 3-6 0.9 4 15 7-10 2.0 5 15 11-14 1.8 5 25 3-6 3.0 5 25 7-10 2.6 3 25 11-14 3.5 Zhu et al 2004 14 Mean 16 Mean 5.4 0.78

33. 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

34. 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

35. 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)

38. 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 AdultsChild SS 24.918.36 10.948.60 FS 15.38 8.25 8.705.13 FF 8.14 5.37 6.033.94

39. 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

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

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

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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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.

49. 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

50. 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