5. New-repurposed Tb Drugs In Children - Garcia-prats.pdf

Use of the shortened treatment regimen and new/repurposed drugs for MDR-TB among children: global evidence and recommendations Anthony “Tony” Garcia-Prats Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University [email protected]

Overview 

Choice of MDR-TB regimen • Approach to choosing/evaluating a regimen • Shortened regimen

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Emerging evidence in children for TB drugs • Existing 2nd-line drugs • Novel TB drugs

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Approach to dosing in children Child-friendly formulations

Choosing a regimen for MDR-TB in children 

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Can the shortened regimen (9-11 months) be used in children? Approach to recommending TB drugs and regimens for children?

Approach to study of TB treatment in children (1) 

Evidence for TB treatment regimens in children based on adult studies • Challenges of evaluating efficacy of TB treatment in children • TB in children usually paucibacillary – tends to respond better to treatment

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Paediatric evidence needed • Dosing in children that gives same concentrations as in adults • Safety in children at that dose

Shortened (9-11m) regimen for MDR-TB 

Observational data • Multiple prospective cohort studies in adults with MDRTB • Successful treatment outcomes: 

87.9% (95% CI 82.7, 92.6) (n=206) • Van Deun, et al. Am J Respir Crit Care Med Vol 182. 684–692, 2010

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84.5% (95% CI 0.81, 0.88) • Aung et al, IJTLD 18(10):1180–1187, 2014

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WHO Recommendation in 2016

Shortened (9-11m) regimen for MDR-TB 

STREAM 1 Trial • Randomized clinical trial – adults with MDR-TB • 9-11m regimen vs standard (20-24m) • Preliminary results STREAM 1 Favorable

Unfavorable 95% CI

Study arm (N)

Control (N)

78.1% (164)

80.6% (87)

21.9% (46)

19.4% (21)

-6.9%, 11.2%

The shortened (9-11 month) regimen for children with MDR-tB 

Limited data in children • 47 children <18 y (West African cohorts) • 83% successful outcomes

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No reason to expect it would not work in children Appropriate to use in children for the same criteria as in adults

Flouroquinolones safety - Overview (1) 

Central nervous system

• Caffeine-like effects – sleep disturbance, hyperactivity • Nightmares, hallucinations

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Cardiac

• QT interval prolongation • Mfx > Lfx • Limited experience in children

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Others

• Dermatologic, GI disturbance, ophthalmologic

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Arthropathy

Fluoroquinolone safety (2) 

Juvenile animal data

• Burkhardt JE, Walterspiel JN, Schaad UB. Quinolone Arthropathy in Animals Versus Children. Clinical Infectious Diseases. 1997;25(5):1196-204.

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Articular cartilage damage seen in all juvenile animals studied Severe arthropathy in dogs • Weight-bearing joints • Tended to result in some degree of permanent disability • Did not resolve completely

Fluoroquinolone safety (3) 

Safety with short term use in children • Burkhardt JE, et al. Clinical Infectious Diseases. 1997;25(5):1196-204. 

Review of >7000 children – no evidence of severe arthropathy

• Yee CL, et al. Pediatr Infect Dis J. 2002;21(6):525-9. 

6,000 children – no difference in tendon/joint disorders among fluoroquinolone vs azithromycin treated children

• Noel GJ, et al. Pediatr Infect Dis J. 2007;26(10):879-91. 

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>2000 children – reports of arthralgia were slightly higher in fluoroquinolone treated children Risk of bias (subjective reports)

Baseline characteristics (n=70) N (%) Median age in years (range)

2.1 (0.4-7.3)

Age at enrolment 0 to <2 years 2 to <6 years 6 to <15 years

31 (44%) 35 (50%) 4 (6%)

Male sex

38 (54%)

HIV-infected

12 (17%)

Weight-for-age Z-score < -2

16 (23%)

Person-years of observation Total, in years Median, in months (IQR)

68.5 11.6 (9.2-14.7)

Results (1): All adverse events Adverse event by grade # of total # Event Rate patients Adverse Event Grade 1 Grade 2 Grade 3 Grade 4 of (per personwith events yrs) event Arthralgia 3 3 0 0 0 3 0.044 Arthritis 0 0 0 0 0 0 -Pain other than traumatic injury 11 11 0 0 0 11 0.161 Headache 4 4 0 1 0 5 0.073 Neurosensory alteration 1 1 0 0 0 1 0.015 Insomnia 1 0 1 0 0 1 0.015 Fatigue/malaise 1 1 0 0 0 1 0.015 Nausea 12 13 0 0 0 13 0.190 Vomiting 19 23 1 0 0 24 0.351 Anorexia 11 8 5 0 0 13 0.190 Cutaneous reaction 12 8 6 0 0 14 0.204 Pruritus 13 16 1 0 0 17 0.248 Acute systemic allergic reaction 0 0 0 0 0 0 -ALT 22 17 3 2 5 27 0.394 Bilirubin 0 0 0 0 0 0 -# of events may exceed # of patients with event, as patients may have had more than one event

Results (2): Adverse effects at least possibly related to levofloxacin Adverse effects possibly, probably, definitely attributed to levofloxacin # of total # Event Rate patients Adverse Event Grade 1 Grade 2 Grade 3 Grade 4 of (per personwith events yrs) event Arthralgia 2 2 0 0 0 2 0.029 Arthritis 0 0 0 0 0 0 -Pain other than traumatic injury 4 4 0 0 0 4 0.058 Headache 2 1 0 1 0 2 0.029 Neurosensory alteration 0 0 0 0 0 0 -Insomnia 1 0 1 0 0 1 0.015 Fatigue/malaise 0 0 0 0 0 0 -Nausea 8 9 0 0 0 9 0.131 Vomiting 14 16 0 0 0 16 0.234 Anorexia 7 4 3 0 0 7 0.102 Cutaneous reaction 7 3 4 0 0 7 0.102 Pruritus 7 7 1 0 0 8 0.117 Acute systemic allergic reaction 0 0 0 0 0 0 -ALT 16 16 2 0 0 18 0.263 Bilirubin 0 0 0 0 0 0 -# of events may exceed # of patients with event, as patients may have had more than one event

Levofloxacin safety with long-term dosing in children: other data 

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Seddon JA, Hesseling AC, Finlayson H, et al. Preventive Therapy for Child Contacts of Multidrug-Resistant Tuberculosis: A Prospective Cohort Study. Clinical Infectious Diseases. 2013;57(12):1676-84. Garcia-Prats AJ, Draper HR, Thee S, et al. Pharmacokinetics and safety of ofloxacin in children with drug-resistant tuberculosis. Antimicrobial Agents and Chemotherapy. 2015;59(10):6073-9. Garcia-Prats AJ, Draper HR, Finlayson H, et al. Clinical and cardiac safety of long-term levofloxacin in children treated for multidrug-resistant tuberculosis. Clinical Infectious Diseases. 2018 (in press).

Discussion 

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Levofloxacin was generally safe and well tolerated at 10-20mg/kg once daily dose Limitations • Over-reported some events - i.e. ALT, vomiting • May have under-reported mild arthralgia • May have under-reported CNS effects

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Conclusion: Levofloxacin safe and well-tolerated at currently used does even for long durations in children, and should be used as recommended for MDR-TB treatment and prevention

Levofloxacin dosing 

15-20 mg/kg once daily • Still low AUC • Safe at this dose • 15-20 mg/kg once daily • No effect of crushing, but formulation may make a difference

Moxifloxacin dosing 

In younger children, 10mg/kg dose resulted in low exposures relative to adults (400mg) • 10-15 mg/kg dose for now • No effect of crushing • Poorly palatable

Amikacin dosing: Summary PK Mondongo et al. 2016

MDRPK1 Dose

15 mg/kg

20 mg/kg

750 (500-1000)

Cmax (μg/mL)

34.9 (21.2-50.5)

45.0 (19.3 – 72.2)

≈ 44 (22-66)

Tmax (μg/mL)

1.0 (1.0 – 2.0)

1.0 (1.0 – 2.0)

89.9 (58.4 – 138)

124.2 (44 – 205.3)

1.4 (0.8 – 2.4)

1.5 (0.9 – 2.5)

AUC(0-8) (μg/mL) T1/2 (μg/mL)

≈ 550 (364 – 725)

Amikacin dosing: conclusions 

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Age influenced AUC, not Cmax Empiric dose of 18-20mg/kg 20mg/kg should not be routinely exceeded • TDM • Risk of hearing loss

Linezolid 

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Highly effective anti-TB drug Frequent, serious dose- and duration-related adverse effects

• Cytopaenias, peripheral neuropathy, optic neuropathy, others

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Indications

• As per guidelines • MDR TB meningitis

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Dose:

• <30 kg - 10 mg/kg twice daily • >30 kg – 600 mg once daily

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Careful monitoring – FBC monthly

Clofazimine 

Recommended dose: 2-4 (or 5) mg/kg/day • Formulations: 50 mg and 100 mg soft gel caps

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PK data in children:

• ???? • Planned paediatric study, seeking funding

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In practice

50 mg gel caps

100 mg gel caps

1 cap alternative days

1 cap every 3rd day

10 to <20 kg

1 cap daily

1 cap alternative days

>20 kg

2 caps daily

1 cap daily

5 to <10 kg

Novel TB drugs in children   

Delamanid paediatric trials - update Bedaquiline paediatric trials – update Practical guidance

Otsuka trials 232 and 233 (2)

Enrollment Enrollment Ongoing Completed

Enrollment Completed

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232 – Phase 1, 10 days DLM 233 – Phase 2, 6 months DLM Current Tablet Formulation

• Group 1: Adolescents 12 to 17 years 

(100 mg BID; n=6)

• Group 2: Children 6 to 11 years 

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(50 mg BID; n=6)

Pediatric formulation

• Group 3: Children 3 to 5 years 

(25 mg BID; n=12)

• Group 4: Newborns and infants 0 to 2 years  

[10mg BID (>10kg), 5mg BID (>8 to 10 Kg), 5mg QD(5.5 to 8Kg] (n=12) Slide provided by Jeff Hafkin, Otsuka Pharmaceuticals 23

Delamanid Median Plasma Concentrations (ng/mL)

Otsuka 232/233: Phase I/II studies of delamanid in children with MDR-TB

1400 1200 Max (Trial-208)

1000

800 Group 1 (100mg BID) Trial-208 (100mg BID) Trial-208 (100mg BID) Max

600 400

Min (Trial-208)

200 0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

Time (Weeks)

Presented at Union Meeting 2015 (Cape Town, SA), Jeff Hafkin, Otsuka Pharmaceuticals

24

Delamanid: conclusions 

Otsuka 232/233 • Groups 1-3 fully enrolled, 232 data analyzed • Group 4 enrolled, follow-up ongoing • Pediatric dispersible formulation

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Delamanid exposures in children 3-17y were within adult ranges with proposed dosing; safe WHO guidance for children 6-<18y

Phase I/II pediatric bedaquiline trials C211: Bedaquiline PK and safety in HIV-uninfected children (n=60)

P1108: PK, safety and tolerability of bedaquiline with OBR in HIVinfected and uninfected children with MDR-TB (n=54-72)

Sponsor

Janssen Pharmaceuticals

NIH (DAIDS, IMPAACT)

Design

Age de-escalation

Modified age de-escalation

Inclusion

0-<18y, HIV-uninfected only

0-<18y; both HIV-infected and uninfected

Accrual

Open 2106, South Africa, Philippines, Russia, India

Open 2018 – South Africa, India, Haiti

Other

Adult, pediatric formulations

Adult formulation, ? pediatric formulation

Practical use of BDQ and DLM in children with MDR-TB  

Same indications as adults (additional 2nd-line resistance or intolerance) Bedaquiline • >12y and >33 kg – adult dose • <12y or <33 kg – case-by-case • Crushed/”dissolved” tablet can be used

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Delamanid • • • •

>35 kg – 100 mg twice daily 20 to <35 kg – 50 mg twice daily 10 to 20 kg – 25 mg twice daily <10 kg – case-by-case basis

Dosing 2nd-line TB drugs in children: Challenges??

Dosing 2nd-line TB drugs in children 

Dose changes with weight/age • Use weight-banded dosing

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Limited data on PK of 2nd-line TB drugs in children • Ongoing and future studies

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Lack of child friendly formulations - Challenging to accurately dose, and decreases palatability

• Ensure accurate and pragmatic dose considering available formulation • Provide anticipatory guidance to parents • Follow-up dosing method and accuracy each visit • Ultimately…child friendly formulations

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Offer empathic support to child and caregiver

Child-friendly formulations Product Name Pyrazinamide 150 mg DT Ethionamide 125 mg DT RH 75/50 RHZ 75/50/150 Levofloxacin 100 mg DT Moxifloxacin 100 mg DT Cycloserine 125 mg capsules Ethambutol 100 mg DT

Status of WHO or ERP Approval WHOPQ WHOPQ WHOPQ WHOPQ ERP approved ERP approved ERP approved Under assessment in WHOPQ

Isoniazid 100 mg DT Linezolid 150 mg

Not filed in WHO Not filed in WHO

EARLY EXPERIENCES OF THE ACCEPTABILITY AND PALATABILITY OF A NOVEL CHILD-FRIENDLY LEVOFLOXACIN FORMULATION IN YOUNG CHILDREN S Purchase1, A Garcia-Prats1, D Wademan1, G Hoddinott1, P De Koker1, H Draper1, J Seddon1,2, HS Schaaf3, AC. Hesseling1 The 48th Union Conference, Guadalajara, Mexico, 2017

Caregiver’s perceptions of palatability

13/27 (48%) of caregivers felt that their children liked/really liked the taste of the tablets. Only 7/27 (26%) disliked the taste.

Caregiver’s comparison of study drug taste with taste of previous TB medication

18/26 (81%) of caregivers felt that taste of the new formulation was equivalent/better/much better than taste.

Caregiver’s perceptions of ease of preparation

26/27 (96%) of caregivers indicated that the preparation of doses was easy/very easy.

Caregiver’s comparison of study drug preparation with preparation of previous TB medication

22/26 (85%) of caregivers felt that preparation of the new formulation was better/much better than preparationn.

Conclusions 

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Shortened regimen may be used in children for same indications as in adults Dosing of 2nd-line drugs should follow emerging data BDQ (12 yo and older) and DLM (3 yo and older) may be used in children, or in younger on case-by-case basis Weight-banded, practical approach to dosing Child-friendly formluations exist, are beneficial, and can be procured from GDF

Acknowledgments 

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Simon Schaaf, Anneke Hesseling, Desmond Tutu TB Centre National TB Programme, KNCV/Challenge TB, other partners