Current status of pharmacokinetic and safety studies of multidrug-resistant tuberculosis treatment in children

Abstract

After decades of neglect, data are finally becoming available on the appropriate, safe dosing of key second-line anti-tuberculosis drugs used for treating multidrug-resistant tuberculosis (MDR-TB) in children, including levofloxacin (LVX), moxifloxacin (MFX), linezolid (LZD) and delamanid (DLM). Much needed data on some novel and repurposed drugs are still lacking, including for bedaquiline (BDQ), pretomanid (PTM) and clofazimine (CFZ). We review the status of pharmacokinetic (PK) and safety studies of key anti-tuberculosis medications in children with MDR-TB, identify priority knowledge gaps and note ongoing work to address those gaps, in the context of planning for an efficacy trial in children with MDR-TB. There is international consensus that an efficacy trial of a novel, all-oral, shortened MDR-TB treatment trial in children is both needed and feasible. Key novel and repurposed second-line anti-tuberculosis drugs include BDQ, DLM, PTM, MFX, LVX, CFZ and LZD. The rapidly emerging PK and safety data on these medications in children with MDR-TB from studies that are underway, completed or planned, will be critical in supporting such an efficacy trial. Commitment to addressing the remaining knowledge gaps, developing child-friendly formulations of key medications, improving the design of paediatric PK and safety studies, and development of international trial capacity in children with MDR-TB are important priorities.

Towards tailored regimens in the treatment of drug-resistant tuberculosis: a retrospective study in two Italian reference Centres

“…On the other hand, the median length of the regimens was 18 months reflecting the possibility, in the future of shorter anti-MDR and pre-XDR-TB regimens in case of localized disease, with rapid culture conversion, radiological improvement, clinical stability and good tolerance to treatment [12–20]. Regimens containing linezolid were associated with a better outcome, supporting the recent upgrade of this drug in the recent WHO guidelines [11, 19, 21]. Furthermore, meropenem/clavulanic acid containing regimens, even if burdened by intravenous administration, showed statistically significant benefits [22].…”

Twenty‐four‐week interim outcomes of bedaquiline‐containing regimens in treatment of adolescents with rifampicin‐resistant tuberculosis: A retrospective cohort study in China

“…The priority for paediatric trials of anti-TB drugs is to perform pharmacokinetic studies to identify the doses in children that result in exposures approximating those in adults receiving the recommended dose, and to establish safety in children at those doses. 25 Despite the global roll-out of and increasing access to bedaquiline for adults, to the best of our knowledge, there are no pharmacokinetic data for children and adolescents. The current study explored the pharmacokinetics related to bedaquiline in adolescents with RR-TB for the first time.…”

Practical and psychosocial challenges faced by caregivers influence the acceptability of multidrug-resistant tuberculosis preventive therapy for young children

“…TB-CHAMP is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts (<5 years of age) of MDR-TB implemented at three sites in South Africa [ 28 ]. Before the trial began, the study team conducted a pharmacokinetic lead-in study to determine appropriate dosages and preliminary palatability and acceptability of the novel levofloxacin formulation in 27 children [ 17 , 28 , 29 ]. Although an internationally accepted standard approach to preventive therapy for children exposed to MDR-TB does not exist, a regimen consisting of levofloxacin (adult 250 mg formulation), ethambutol and high-dose isoniazid is prescribed to children exposed to MDR-TB in Cape Town [ 17 ].…”