ANNEKE C. HESSELING

PROFESSOR IN PAEDIATRICS AND CHILD HEALTH

DIRECTOR: DESMOND TUTU TB CENTRE

DEPARTMENT OF PAEDIATRICS AND CHILD HEALTH

STELLENBOSCH UNIVERSITY, SOUTH AFRICA

TUBERCULOSIS PK 2018

WHO CHILDHOOD TB MEETNG

23 OCTOBER 2018, DEN HAAG

PAEDIATRIC TB TRIAL UPDATE

http://www.fda.gov.ezproxy.nihlibrary.nih.gov/downloads/Drugs/

Research Area

Gaps for children Priority studies

DS-TB • Dose optimization (rifampicin)

• Treatment of Severe TB

• Treatment shortening: non-severe TB

• PK studies first-line drugs at higher doses: OptiRif Kids

• PK/efficacy study in children: SURE, TBM-Kids

• SHINE

DR-TB • PK/dosing second-line drugs (FQ, aminoglycosides, linezolid, clofazimine, hd INH)

• New drugs: PK and safety (bedaquiline, delamanid, PA-824, sutezolid)

• Injectable sparing shorter regimen

• Modeling existing data, testing doses predicted to achieve PK targets

• PK/safety studies bedaquiline, PA-824, DLM, BDQ and combinations: MDR PK1, MDR PK2

• P1108, C211, Otsuka 232/233, P2005

• IMPAACT 2020 (SMART-Kids)

Co-treatment TB/HIV

• Super boosting LPV/r in young children taking HRZE

• EFV-based regimen in children < 3 years • INSTI-based ART with standard TB drugs

(HRZE)

• DnDI: Super-boosted PI with HRZE • EFV+HRZE in slow CYP2B6

genotype • RAL or DTG-based ART with TB

drugs: Odussey

LTBI • 3 HP: Safety/tolerability/PK once-weekly • 1 HP: Safety/tolerability/PK once-weekly

• MDR-TB prevention

• MDR TB prevention

• TBTC Study 35 • CAP 543

• Efficacy and safety: TB CHAMP, V-

QUIN, PHOENIX: phase III

3

N=1200 children New FDC; 75, 50, 150 (McCleods)

Status: n=1204 patients enrolled: f/u ongoing: results early 2020

“non-severe TB” only

DEFINITION OF TARGET PK DRIVERS OF TREATMENT RESPONSE

RIFAMPICIN PYRAZINAMIDE ISONIAZID

Cmax AUC Cmax AUC Cmax AUC

Model-based Cmax and AUC estimates in first 47 children enrolled to the DATiC study (Zvada et al. 7th Int WS TB Pharm 2014; Chigutsa et al. AAC 2015).

Boeree, AJRCCM, 2015

Study design

Rifampicin ~ 20 mg/kg

Day 1 7 14 15

PK PK PK

HD

Standard RHZE Standard RHZE Standard HZE

Single high-dose

rifampicin

~35mg/kg

Monitoring for adverse events

0, 1, 2, 4, 6, 8, 24 h 0, 2, 4, 8, 24 h n = 20 per cohort

0-12 years

See Svensson et al, Union oral

•Dosing cohorts: n=20 per cohorts: A minimum of 60 (20 children per cohort) and a maximum of 100 evaluable child participants (i.e. 5 dosing cohorts) enrolled •At least 3 dosing cohorts required, to demonstrate exposures in children similar to those achieved in adults receiving 35-40 mg/kg in HIGHRIF1 •No age de-escalation. Children enrolled in 3 age groups, with children in all 3 age groups included in each dosing cohort:

• Age group 1: Age ≥ 6 to < 12 years: completed • Age group 2: Age ≥ 2 to < 6 years: completed • Age group 3: Age ≥ 0 to < 2 years: open (October 2018)

OptiRif Kids

MDR-TB in adults: low Treatment Success and High Mortality

10

MDR TB: 50% treatment success, 16% death XDR TB: 24% treatment success, 30% death

WHO Global TB Report 2015

Global MDR-TB treatment outcomes in children

Seddon, Clin Infect Dis 2013

Table3.Summaryoftreatmentoutcomesforchildrenwithmultidrug-resistanttuberculosis

Clinicallydiagnosed

MDR-TB

n=238

ConfirmedMDR-TB

withoutconfirmed

XDR-TB

n=701

ConfirmedXDR-TB

n=36

Cured 0 327(46.6%) 23(64%)

Completedtreatment 166(69.7%) 209(29.8%) 7(19%)

Failorrelapse 0 14(1.9%) 1(3%)

Death 7(2.9%) 73(10.4%) 3(8%)

Lost-to-follow-up 19(8%) 77(11%) 2(6%)

Harausz et al, PLOS Med 2018 *76.4%

*

Update planned: 2019

Individual drugs gaps: MDR TB trials Keysecond-lineTBdrugs,keyknowledgegapsinchildrenandongoingorplannedpaediatricstudies

Drug Current Keygaps Ongoing/plannedstudiesLevofloxacin PKdatainTBacrossages;low

exposures

Optimaldoseandsafety;

formulation

MDRPK1,MDRPK2

Moxifloxacin PKdatainTB,>8yonly;lowexposures

PKdatain<8y;optimaldoseandsafety;formulation

MDRPK1,MDRPK2(interimanalysisongoing)

Bedaquiline NoPKdata PKdata,optimaldose,safety;HIV

P1108;Jannsen-trial;IMPAACTcapsule(BDQ-

DLM)Delamanid PKdata>6y PKdatainchildren<6y,

safety;HIVOtsuka232/233;IMPAACT2005;IMPAACTcapsule(BDQ-DLM)

Linezolid PKdatainnon-TBacrossages PKdatainTB,optimaldose,

safety;formulation

MDRPK2(interimanalysis

ongoing)Clofazimine LimitedpublishedPKdata PKdata,safetyoptimaldose;

formulation??–IMPAACTCapsule

Pretomanid: No data; PIP in progrres PK, safety, formulations ?2019

MDR-TB: phase I/II paediatric bedaquiline trials

C211: Bedaquiline PK and safety in HIV-uninfected children (n=60)

P1108: PK, safety and tolerability of bedaquiline with OBR in HIV-infected 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

Progress Data from cohort 1 (12-17y) shared with WHO

Data from cohort 1 (6-17y) shared with WHO

IMPAACT P1108: Phase I/II: PK, safety and tolerability of bedaquiline in HIV-infected and uninfected children with MDR-TB • Modified age de-escalation trial: 0-17 years; n=54

• Dose-finding; pharmacometric modeling, dose adjustment; adaptive design, semi-real time modeling

• Younger cohorts open in parallel (0-2 and 3-5 years)

• Adult formulation: whole/crushed

• Long-term safety; treatment outcome

P1108 Interim pharmacokinetics analysis

BDQ CRUSH

Design Randomized open-label two-period crossover study

Objectives Primary: To evaluate BA of whole vs crushed BDQ Secondary: To characterize 1) rate of absorption, 2) short term safety, 3) acceptability of whole vs crushed BDQ

Setting TASK (Cape Town, SA); Sponsor – DAIDS/IMPAACT

Patients Healthy adult volunteers

Dosing Sequence 1: 4 x 100 mg BDQ whole, then 4 x 100 mg BDQ dissolved, both with food Sequence 2: 4 x 100 mg BDQ dissolved, then 4 x 100 mg BDQ whole, both with food

Assays UCT – HPLC-MS/MS for BDQ and M2

Analysis NLME (primary endpoint = bioavailability parameter)

BDQ CRUSH: impact of dissolving on a typical BDQ PK profile

• Mean absorption time

slightly longer for

dissolved tablets: +23%

(p=0.03, CI95% 2.1-48%)

• Tmax: 4.3 to 5.2h

• Cmax: 5%

Difference in bioavailability dissolved vs whole tablets not statistically significant (p=0.92, CI95% 94-108%) Bioequivalence criteria fulfilled

Analysis and slide courtesy of Elin Svensson

Delamanid: 232 and 233: Median delamanid and DM-6705 plasma PK parameters for Groups 1-3 in pediatric trial 232

Group 1 (12 – 17y)

(n=7)

Group 2 (6-11y) (n=6)

Group 3 (3-5y) (n=12)

Adults

Median DLM Cmax

(ng/mL) 557 573 500 357

Median DLM AUC0-24

(ng*h/mL)

9730 12000 9085 6811

Median DM-6705 Cmax (ng/mL)

81.7 90 69 114

Median DM-6705 AUC0-24 (ng*h/mL)

1780 1870 1374 2411

*Day 10 values from 232 for Groups 1 and 2; Day 14 values from adult trials

Novel TB drugs in children

Delamanid Children 6-17y – same

indications as in adults Children <6y – case-by-case

basis Access? DLM CRUSH?

Bedaquiline Children >12y – same

indications as in adults Children <6y – case-by-case

basis Access in younger kids? Watch “this” space

IMPAACT 2020 (SMaRT Kids)

Design: Phase 2 multi-centre trial

Eligibility Children 0 to <15 years of age;

Probable or confirmed pulmonary or extrapulmonary MDR/RMR-TB/Rif-R, and MDR-TB with additional SLI-res or FQN-res

HIV-infected and uninfected

Exclusion - Probable or confirmed Stage 2 or 3 TB meningitis or osteoarticular TB

Assignment to 1 of 2 arms based on FQN-susc Arm 1 – FQN-Susc – 26 weeks BDQ-DLM-Levo, 8 weeks Lzd

Arm 2 – FQN-Res – 26 weeks BDQ-DLM-CFZ, 8 weeks Lzd

Objectives – 1o - Safety; 2o - outcomes, PK, others

N=148

New WHO recommended regimens: DS-TB

WHO LTBI Guidelines,

March 2018

Evidence gaps: shorter regimens: DS-TB

• 3HR: Rigorous implementation science needed to guide optimal and cost effective implementation of 3HR- including health systems strengthening (FDCs to support preventive therapy already WHO prequalified)

• 3HP: PK and safety data on rifapentine and INH (12 doses over 12 weeks in total) : TBTC Study 35 in 0-12 years (HIV+/-) will open in Q1 2019 under FDA IND, for licensure, with Sanofi: will include HIV+ (EFV, DTG)

• 1 HP: Paediatric PK and safety data needed (HIV-/+): IMPAACT 543

• 1 HP vs. 3 HP?: Safety, completion: PROTEA

• 4 R: any need for paediatric data?

TB-CHAMP V-QUIN PHOENIx

Intervention LVF vs. placebo daily for 6 months

LVF vs. placebo daily for 6 months

DLM vs. standard dose INH daily for 26 weeks

Target Population <5 years regardless of IGRA or HIV status Only study powered for efficacy in children

• All ages • TST + • Children not yet

treated

• HIV + • Children <5 years • TST/IGRA + >5

years

Sample size 778 Households 1556 contacts < 5 y

1326 Households 2785 contacts

1726 Households 3452 contacts

Sites South Africa DTTC, Shandukani, PHRU Matlosana

Viet Nam NTP

ACTG & IMPAACT sites

Timelines Open; n=230 enrolled

Open ; 70% enrolled Q1 2019

Funder, PI BMRC/Wellcome Trust/DFID, SA MRC SHIP; Hesseling MRC CTU at UCL

Australian MRC Fox, Nguyen SA NTP

DAIDS, ACTH/IMPAACT Churchyard, Gupta, Hesseling, Swindells

TB-CHAMP

Cluster randomised phase III superiority trial of Levofloxacin vs. placebo for the prevention of TB in child contacts of DR-TB index cases

Levofloxacin 15-20 mg/kg vs. placebo, 6 months: n=1556

Novel formulation: 100 mg scored dispersible

“A deterioration in the control of TB thus immediately hurts the youngest

generation”

Rieder, 1997

Last Update: 10/26/2012 Printer Friendly Email This Page Download Adobe Reader

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