Second-line and novel TB drugs in children: emerging data and research update Anthony J. Garcia-Prats, M.D., MSc. [email protected]Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University Childhood TB Training Course September 12, 2017
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Second-line and novel TB drugs in children: emerging data and research update
Anthony J. Garcia-Prats, M.D., MSc.
[email protected] Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University
• Knowledge gaps and planned studies of existing second-line and novel TB drugs in children
• Other issues
• Phase 3 trials in children
• Conclusion
• Question 1: In developing TB drugs for children, the following aspects are critical to study in children themselves (may select more than one):A. Safety (the medicine is safe in children)
B. Pharmacokinetic (the medicine achieves target exposures/concentrations)
C. Efficacy (the medicine kills TB)
D. Acceptability (the medicine is acceptable to children/parents)
• Question 2: Which of the following statements accurately describe ethical considerations for studying novel TB drugs in children (may select more than one)?A. It is unethical to study new medications in children because the risk is too high
B. New medications should be studied in children along with adults from the very beginning of drug development
C. Adolescents can be included in later phase adults studies (Phase 2b/3, after some efficacy/safety demonstrated)
D. Once reasonable efficacy and safety has been demonstrated in adults, well planned paediatric studies should begin
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– Challenge with confirming a diagnosis
20mg/kg vs 15mg/kg dose Still low AUC Safety data at this dose 15-20 mg/kg once daily
More optimal doses May improve outcomes further Facilitate shorter or injectable sparing regimens Important for bridging to novel regimens Carefully consider safety
100 mg dispersible tablet formulation (Macleods)
Summary: Moxifloxacin
Class Flouroquinolone
Administration Oral, good bioavailability
Metabolism/elimination
50% metabolized in the liver50% excreted unchanged in the stool/urine
Albumin, to DM-6705Half-life: DM 30-38h; DM-6705 150-600h-
Target AUC in adults after recommended dose
Paediatric dose ??
Data source Otsuka 232 and 233 – Phase I/II study of PK and safety of DM in children with MDR-TB
Otsuka trials 232 and 233
• Otsuka 232 Trial - Phase 1 study of delamanid in children with MDR-TB– PK and short-term safety of delamanid when given for
10 days with OBR
• Otsuka 233 Trial - Phase 2 open-label extension trial – Evaluate the PK and long-term safety of delamanid
when given for 6 months with OBR
• Enrolling in Philippines and Cape Town– Age de-escalation design– HIV-uninfected children ONLY
Table. Median delamanid and DM-6705 plasma PK parameters following 100 mg BID (Group-1) and 50 mg BID (Group-2) delamanid doses in pediatric trial 232
Group 1(12 – 17y)
(n=7)
Group 2(6-11y)(n=6)
Adults
Median DLM Cmax
(ng/mL)557 573 357
Median DLM AUC0-24
(ng*h/mL)9730 12000 6811
Median DM-6705 Cmax
(ng/mL)81.7 90 114
Median DM-6705 AUC0-24
(ng*h/mL)1780 1870 2411
*Day 10 values from 232 for Groups 1 and 2; Day 14 values from adult trials
Otsuka 233: Comparison of Delamanid Plasma Concentration Time Profile in Pediatric (Trial 233) and Adult (Trial 208) MDR-TB Patients
0
200
400
600
800
1000
1200
1400
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Group 1 (100mg BID)
Trial-208 (100mg BID)
Max (Trial-208)
Min (Trial-208)
Del
aman
idM
edia
nP
lasm
a C
on
cen
trat
ion
s (n
g/m
L)
Time (Weeks)
Presented at Union Meeting 2015 (Cape Town, SA), Jeff Hafkin, Otsuka Pharmaceuticals 45
Otsuka 233: Comparison of DM-6705 Plasma Concentrations Time Profile in Pediatric (Trial 233) and Adult (Trial 208) MDR-TB Patients
0
100
200
300
400
500
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Group 1 (100mg BID)Trial-208(100mg BID)
Min (Trial-208)
DM
-67
05
Med
ian
Pla
sma
Co
nce
ntr
atio
ns
(ng
/mL)
Time (Weeks)
Max (Trial-208)
Presented at Union Meeting 2015 (Cape Town, SA), Jeff Hafkin, Otsuka Pharmaceuticals 46
Otsuka 233: Safety, Group 1 (12-17y)
Table 1. Incidence of QT elevation
Category Cut-off (ms)
Group 1 n (%)
New onset QTcF >450 3 (42.9)
>480 0
>500 0
Change in QTcF from baseline
≥30 and ≤60
5 (71.4)
> 60 1 (14.3)
Table 2. Mean [SD] QTcF by study day
Day Group 1
Baseline 407.0 [19.2]
28 423.4 [11.9]
56 417.1 [16.0]
84 427.9 [17.1]
126 428.6 [13.7]
154 423.6 [15.2]
182 420. 8 [16.8]
210 414.2 [8.0]
Presented at Union Meeting 2015 (Cape Town, SA), Jeff Hafkin, Otsuka Pharmaceuticals
Delamanid: conclusions
• Delamanid exposures in children 6-17y were within adult ranges with proposed dosing; safe
• Dosing:
– 20-35kg – 50mg BD
– >35kg – 100mg BD
• Otsuka 232/233
– Group 3 fully enrolled, 232 data anlyzed
– Group 4 enrolling
– Pediatric dispersible formulation
Novel TB drugs: Delamanid
• IMPAACT 2005
– Sponsor: NIH DAIDS/IMPAACT network
– PK and safety of delamanid in HIV-infected and uninfected children (0-<18y) with DR-TB
– Additional information on PK and safety in children
• Include HIV-infected children – DDIs with EFV, LPV/r
• Model-based optimization of dosing
– To open Q4 2017/Q1 2018
Novel TB drugs in children (3): Summary
• Delamanid– Children 6-17y – same
indications as in adults– Children <6y – case-by-
case basis– Access??
• Bedaquiline– Children >12y – same
indications as in adults– Children <6y – case-by-
case basis
Pretomanid
• Similar class of drug to delamanid
• Component of Nix-TB regimen and NC-006
• Toxicity signals have delayed evaluation in children
– Cataracts, testicular toxicity
• No data in children
• Paediatric trials in early development
Overview
• Ground rules and learning outcomes
• Pharmacokinetics – context in childhood TB treatment
• Key concepts in TB drug PK in children
• Emerging data
• Other issues
– Acceptability and formulation
– Weight-banded dosing
• Conclusion
MFX
LFX
Medication acceptability Acceptability
Overall acceptance or suitability of a dosage formulation
Palatability, dose volume or size, dosing frequency, instructions for use
Palatability Acceptance of taste, smell, texture, aftertaste
Current second-line medications
Future?
Overview
• Approach to TB drug trials in children
• Knowledge gaps and planned drug trials
• Other issues
• Phase 3 trials
• Conclusion
Treatment outcomes (1): Adults with MDR-TB
Treatment outcomes (2): Children with MDR-TB
1 Ettehad D, et al. Lancet ID. 2012;12(6):449-56.2 Harausz E, et al. Children treated for MDR-TB – a systematic review and individual patient data meta-analysis. (Union World Conference on Lung Health, 2015)
• 794 of 1012 (78.5%) children with probable or confirmed MDR-TB had successful outcomes2
Approach to studying TB drugs in children
Dunne J, et al. Extrapolation of Adult Data and Other Data in Pediatric Drug-Development Programs. Pediatrics. 2011;128(5):e1242-e9.
TB-CHAMP, SHINE, SMaRT Kids
????
Tuberculosis disease
Latent TBI or non-severe intrathoracic TB
SMaRT Kids: Background and Rationale (1)
• Children with MDR-TB may suffer disproportionately from existing treatment regimens– Hearing loss, interruption of attachment, school– Critical periods of neurodevelopment
• AND would be expected to respond better than adults to shorter, less intense regimens
• Time is right– More children being diagnosed– New and repurposed treatments becoming available
• Children with probable and confirmed MDR-TB stand to substantially benefit from an efficacy trial of a shortened all-oral regimen
– Inclusion• Children 0 to <15 years of age; • Probable or confirmed pulmonary or extrapulmonary MDR/RMR-TB,
and MDR-TB with additional resistance to injectables or fluoroquinolones (i.e. pre-XDR and XDR-TB)
• HIV-infected and uninfected
– Exclusion• Stage 2 or 3 TB meningitis, or osteoarticular TB.
• Sample size: 346 (173 per arm) to demonstrate non-inferior efficacy of intervention arm among children with probable or confirmed MDR/RMR-TB with 90% power
SMaRT Kids: Intervention (3)• Children with MDR/RMR randomized 1:1 to control vs intervention
arms• Children with pre-XDR/XDR assigned to treatment arm based on
resistance profile
Proposed treatment regimens by drug-resistance profile and study arm
MDR/RMR TB
Intervention 2 mo DLM (once daily), CFZ, hdLZD, LFX, PZA / 4 mo DLM (once daily), CFZ, sdLZD, LFX, PZA
Control 4-6 mo KAN/AMK, LFX, PTO/ETO, CFZ, PZA, hdINH, EMB / 5-6 mo LFX, CFZ, PZA, EMB
preXDR/XDR-TB
FQN-susc 2 mo DLM (once daily), CFZ, hdLZD, LFX, PZA / 4 mo DLM (once daily), CFZ, sdLZD, LFX, PZA
FQN-susc 6 mo DLM (once daily), CFZ, hdLZD, PZA, PAS
• Question 1: In developing TB drugs for children, the following aspects are critical to study in children themselves (may select more than one):A. Safety (the medicine is safe in children)
B. Pharmacokinetic (the medicine achieves target exposures/concentrations)
C. Efficacy (the medicine kills TB)
D. Acceptability (the medicine is acceptable to children/parents)
• Question 2: Which of the following statements accurately describe ethical considerations for studying novel TB drugs in children (may select more than one)?A. It is unethical to study new medications in children because the risk is too high
B. New medications should be studied in children along with adults from the very beginning of drug development
C. Adolescents can be included in later phase adults studies (Phase 2b/3, after some efficacy/safety demonstrated)
D. Once reasonable efficacy and safety has been demonstrated in adults, well planned paediatric studies should begin
Conclusion
• Rapidly evolving trial landscape
• Advocate for appropriately timely treatment studies in children and adolescents
• Awareness of emerging data that may influence treatment support
• Commments/questions?
ACKNOWLEDGEMENTS
Anneke Hesseling H. Simon SchaafHelen McIlleron Paolo DentiHeather Draper Adelaide CarelseJennifer Norman Lubbe WiesnerPeter Smith Sandra CastellPeter Donald Marianne WillemseAndre Burger Steffi TheeBrooklyn Chest Hospital team Rada SavicKelly Dooley Jeff HafkinDTTC paediatric teamPatients and their parents
Last Update: 10/26/2012 Printer Friendly Email This Page Download Adobe Reader
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