Is a high dose sufficient to achieve high isoniazid exposure in children affected by multidrug-resistant TB?

Of an estimated 1.2 million children who developed TB in 2019, 5,586 were diagnosed with rifampicin-resistant (RR) or multidrug-resistant TB (MDR-TB; defined as Mycobacterium tuberculosis resistant to at least isoniazid [INH] and rifampicin).¹ Although newer drugs are available and should be used in children and adolescents with MDR-TB,^2,3 many children still receive traditional drugs for MDR-TB treatment or prevention. Much remains to be learnt about optimal TB drug delivery in children,⁴ and while it is generally fair to extrapolate efficacy data from adult studies, safety and pharmacokinetics require careful consideration.⁵

In this issue of the Journal, Winkler and colleagues present results from a pharmacokinetic study on high-dose INH in children affected by MDR-TB, used either as part of a treatment or prevention regimen.⁶ Resistance of M. tuberculosis to INH can be explained in most instances by mutations in either the inhA promoter region, or the katG gene, resulting respectively in low-level resistance and high-level resistance.⁷ Low-level resistance is phenotypically defined by an MIC ranging from 0.1 mg/L to 0.4 mg/L, whereas high-level resistance is defined as an MIC >0.4 mg/L using liquid culture media.⁵ Low-level INH resistance confers a dose-dependent effect, whereby administration of a higher dose can overcome this resistance and still kill the pathogen. Previously reported clinical data from both adults and children suggest that high-dose INH had a positive impact on both microbiological and clinical response.^8,9

Having information on phenotypic INH susceptibility and MIC, or a description of the underlying gene mutations responsible for resistance⁷ is therefore critical when deciding to use high-dose INH for MDR-TB treatment or prevention. However, INH has large inter-individual pharmacokinetic variability related to polymorphisms of the enzyme N-acetyltransferase 2, responsible for the metabolism of INH. Three different polymorphisms (acetylation genotypes) can be distinguished, i.e., fast, intermediate and slow acetylators. The question that requires an answer is whether a higher dose of INH is sufficient to achieve adequate drug exposure to overcome low-level resistance caused by a mutation in inhA across populations of children with variable acetylation status. The need to answer this question has become more urgent since the INH dose for drug-susceptible TB in children was increased by the WHO and it is important to know if the ‘high dose’ definition should be increased proportionally.

Winckler et al. collected multiple timed blood samples from 77 children (median age: 3.7 years) to quantify concentrations of INH and its metabolite N-acetyl-isoniazid and to determine the likely N-acetyltransferase 2 genotype. INH was administered at a dose of 20 mg/kg. The area under the concentration time curve (AUC) was calculated and the highest observed concentration was considered the maximum concentration (C_max). As a target, the authors used the drug exposure associated with optimal early bactericidal activity derived from adults (i.e., an AUC/MIC of 85 and a C_max/MIC of 17).

The investigators were alarmed by the low exposure measured in patients treated for MDR-TB disease but not MDR-TB prevention, although all patients received a high dose of INH. A significant number of patients with MDR-TB disease had an INH exposure at the lower range of what is considered ‘normal exposure’ for a standard dose of INH. In multivariate analysis, the authors were not able to explain differences in drug exposure based on common issues such as sample instability, crushed administration, drug brand, concomitant food intake or clinical condition. The most likely explanation appears to be drug-drug interactions resulting from co-administration of terizidone, a structural analogue of cycloserine, which was administered to all children on MDR-TB treatment, but not to those receiving preventive therapy only. Although more research is needed to elucidate the low INH exposure in children receiving a high dose of INH as part of their MDR-TB treatment, it demonstrates the importance of carefully assessing potential pharmacokinetic differences in children and the risk of new drug-drug interactions when treatment regimens are adjusted.

An earlier study in children showed that younger age, nutritional status and acetylator status were important in explaining INH drug exposure.¹⁰ More recently, low target attainment was demonstrated even with the revised WHO INH dosage recommendations, and malnutrition was associated with a low INH concentration 2 h after drug intake.¹¹ An interesting approach to improve exposure target attainment in children using modelling concluded that not only bodyweight, but also age and nutritional status should be considered in dose selection.¹² With such an approach, more children achieved the target concentration associated with a favourable outcome.¹² One of the questions that remains to be answered is whether such changes to improve drug exposure requires evidence from a randomised controlled trial or whether careful implementation under operational research conditions with appropriate pharmacovigilance would be considered sufficient.³

In conclusion, the study by Winkler et al. highlights the value of therapeutic drug monitoring in children receiving high-dose INH.⁶ This further demonstrates the need to perform routine therapeutic drug monitoring in children to ensure adequate target exposure attainment. Personalised dosing can be justified by the fact that we know what exposure is required to result in effective treatment.⁶ The introduction of innovative point-of-care devices that utilise non-invasive specimens such as saliva^13,14 or urine¹⁵ for semi-quantitative drug exposure assessment offers new opportunities for detecting sub-optimal exposure of critical first- and second-line TB drugs. In addition, a ‘global registry’ for the treatment of MDR-TB in children and adolescents would help collect relevant data under non-trial conditions and enhance our understanding of optimal treatment approaches in this vulnerable population.¹⁶