Bedaquiline for multidrug-resistant TB in paediatric patients

Abstract

BACKGROUND: TMC207-C211 (NCT02354014) is a Phase 2, open-label, multicentre, single-arm study to evaluate pharmacokinetics, safety/tolerability, antimycobacterial activity and dose selection of bedaquiline (BDQ) in children (birth to <18 years) with multidrug-resistant-TB (MDR-TB).METHODS: Patients received 24 weeks’ BDQ with an anti-MDR-TB background regimen (BR), followed by 96 weeks of safety follow-up. Results of the primary analysis are presented based on data up to 24 weeks for Cohort 1 (≥12–<18 years; approved adult tablet at the adult dosage) and Cohort 2 (≥5–<12 years; age-appropriate 20 mg tablet at half the adult dosage).RESULTS: Both cohorts had 15 patients, of whom respectively 53% and 40% of Cohort 1 and Cohort 2 children had confirmed/probable pulmonary MDR-TB. Most patients completed 24 weeks´ BDQ/BR treatment (Cohort 1: 93%; Cohort 2: 67%). Geometric mean BDQ area under the curve 168h values of 119,000 ng.h/mL (Cohort 1) and 118,000 ng.h/mL (Cohort 2) at Week 12 were within 60–140% (86,200–201,000 ng.h/mL) of adult target values. Few adverse event (AE) related discontinuations or serious AEs, and no QTcF >460 ms during BDQ/BR treatment or deaths occurred. Of MGIT-evaluable patients, 6/8 (75%) Cohort 1 and 3/3 (100%) Cohort 2 culture converted.CONCLUSION: In children and adolescents aged ≥5–<18 years with MDR-TB, including pre-extensively drug-resistant-TB (pre-XDR-TB) or XDR-TB, 24 weeks of BDQ provided a comparable pharmacokinetic and safety profile to adults.

What's new in childhood tuberculosis

“…Obstacles to the implementation of these shorter regimens in children include insufficient evidence around safety and dosing schedules. To this end, there is now accumulating data on the safe use of bedaquiline in children and the WHO now recommends its use in both short and long drug-resistant-TB treatment regimens and provides dosing schedules for children of all ages [60 ▪ ]. Similarly, the use of delamanid has been extended to children less than 3 years of age [61].…”

QT Interval Prolongation and Second-line Antituberculosis Medicines in Children: An Update and Practical Considerations for Noncardiologists

“…8 In the ongoing pediatric TMC207-C211 phase 2 study, safety data among 30 children in 2 cohorts (15, 5–10 years and 15, 14–17 years of age) receiving WHO-recommended RR-TB regimens including bedaquiline, indicated that 6 (40%) children had QTcF increase of 30–60 ms from baseline but none had QTcF >460 ms over 24 weeks. 9 In an observational pharmacokinetic study of 15 children and adolescents 6–16 years old receiving bedaquiline-containing regimens for RR-TB in routine care, 2 (13%) had mildly prolonged QTcF up to 480 ms but none had QTcF >500 ms. 10 Interim safety data from another ongoing bedaquiline pharmacokinetic study indicate that 3 (27%) of 11 children <6 years of age receiving RR-TB treatment had QTcF increase of 30–60 ms and all received concomitant clofazimine. 3…”

Telacebec: an investigational antibacterial for the treatment of tuberculosis (TB)

“…For instance, moxifloxacin and levofloxacin, two second-line anti-TB fluoroquinolones also induce QT-prolongation [6]. However, bedaquiline still has an excellent safety profile compatible with the development of a paediatric formulation [7,8]. In 2019, pretomanid, which belongs to the same drug class as delamanid, received approval by the US FDA under its Limited Population Pathway for Antibacterial and Antifungal Drugs.…”