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Second-line TB drugs: ‘It is more difficult to assess adverse effects in children’

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The success rate of treating children with MDR-TB has been excellent compared with adults

H. Simon Schaaf:“It is more difficult to assess adverse effects in children compared with adults.”— Photo: Special Arrangement
H. Simon Schaaf:“It is more difficult to assess adverse effects in children compared with adults.”— Photo: Special Arrangement

Prof. H. Simon Schaaf , a clinical researcher from the Department of Paediatrics and Child Health, Faculty of Health Sciences, Desmond Tutu TB Centre, Stellenbosch University, South Africa has worked extensively on childhood TB and multi-drug resistant TB (MDR-TB) in children. Last year he was awarded an A-rating by the National Research Foundation, South Africa. A-rating is the highest award given to scientists by the Foundation. This award was in recognition of his excellence in research in paediatric TB and MDR-TB in children.

In an email, Prof. Schaaf explained to R. Prasad the central issues related to pharmacokinetics and paediatric drug development of second-line anti-TB drugs to treat MDR-TB.

Are higher doses (for first-line drugs) recommended for children, including those younger than five years, because they have higher metabolism or higher drug clearance than adults?

If children are given the same dosage in mg/kg as adults for most of the first-line drugs, the drugs do not reach the same concentration in their [children’s] blood when compared with adults. Children also seem to clear the drugs faster from the body compared with adults.

The reason for this may be multiple e.g. more body water, liver bigger in comparison to body size in children compared to adults, less damage to organs. In very young babies this is most likely different, as their bodies may still be developing into full function, therefore we should also specifically study these very young babies to give them the correct dosage for their age.

Have pharmacokinetics, adverse effects and toxicity been well understood for first-line drugs for infants and children younger than five years, after WHO revised the dosing?

I think the pharmacokinetics/pharmacodynamics have been reasonably well studied and we know about the adverse effects and toxicity of the drugs. We should, however, remember that this may differ with different drugs in different population groups, for example, with isoniazid (INH) in the South African population who are mainly fast acetylators (breaking down and eliminating the drug faster) of INH it is different to that in the Indian population, in which most of the people are slow acetylators (taking longer to break down and eliminate the drug) of INH. These kind of differences, not only in population groups, but also at different ages and in combination with different other drugs still need to be studied in many instances.

Have these three factors been studied in the case of second-line drugs for children, especially infants and those younger than five years?

No. Very little is currently known about especially pharmacokinetics and pharmacodynamics of the second-line anti-TB drugs in children. We are aware of the adverse effects and toxicity of these drugs, but are still evaluating how common these are specifically in children (it seems to be less than in adults).

We are also currently doing pharmacokinetic studies in children of these drugs in Cape Town, South Africa, but these may need to be repeated in different populations to see whether there are important differences in populations.

Will treating children with second-line drugs cause more morbidity in them? Does science allow their use in the absence of evidence?

These are difficult questions. Dosages in children have been derived mainly from adult studies and thus far children have rather been underdosed than overdosed using these recommendations. However, the success rate of treating children with MDR-TB has been excellent compared with adults. In a meta-analysis published in 2012 of treatment outcome of children with MDR-TB more than 80 per cent were successfully treated, while in adults the success rate is often between 45-65 per cent.

Fortunately, our own experience is that children have fewer adverse effects compared with adults with the same drugs, but it is essential to find the correct balance between effective dosage and minimum possible adverse effects of any drug — and this is what we are aiming for.

In the past it was difficult to do pharmacokinetic studies in children, and this often lead to ‘off-label’ use of drugs in children, but new regulations in many countries now emphasize the importance of doing drug studies in children in the development of new drugs. With the older drugs, often used in MDR-TB, their use is important to save lives — it becomes a choice of using the drugs (which are relatively safe through experience) or losing the child.

Do we have adequate drugs and child-friendly second-line drugs to treat MDR-TB diseased children? Is it correct to break, crush or powder tablets meant for adults to treat children? Will such acts not affect the tablets’ effectiveness?

If we use the current drugs we have to the best of our ability and diagnose MDR-TB in time, by far the majority of children will be cured, despite fact that we have to cut, crush and dissolve adult-type tablets. However, it is difficult for doctors, health care workers and caregivers to work with the mostly not child-friendly drugs, and mistakes can easily be made.

We currently do not have enough knowledge about the second-line drugs to know the effect of breaking crushing and dissolving the drugs have on harmacokinetics or pharmacodynamics of these drugs — this is part of what we are studying. Children are getting cured despite these problems, but it is essential that we need to develop child-friendly drugs for the benefit of children and everyone caring for them.

Isn't there a high probability of over- or under-dosing when we break, crush or powder tablets ?

Yes, it is a possibility but needs to be studied. It also depends on the accuracy with which the doctors, health care workers and caregivers prescribe and administer the drugs.

As the adverse effects and other parameters have been studied, will it take a long time for drug companies to produce child-friendly formulations?

We need to put pressure on drug companies to develop such drugs, as of their own they usually are not interested in small markets such as children with drug-resistant TB because it does not make money for them. Developing dispersible formulations (syrup/suspensions — which are also not ideal, as often needs refrigeration, bottles, which can break, and have short shelf-lives) takes time, as it is a complete new development of the active drug with other substances to eventually form a formulation that can be dispersed/dissolved in water and is stable, last long enough on the shelf as well as taste good for children.

Once this is developed, bioavailability studies have to be done in healthy adult volunteers and only then can it be tested in children before it can eventually be registered and marketed — all of this can take several years. As advocates for children, we need to get the companies to start doing this.

Is it possible to produce fixed-dose, combination drugs for second-line drugs for children?

This is something to be thought through very carefully. We mainly make use of individualised MDR-TB treatment, that is, we build a combination of drugs which is suitable for a specific child according to the drug-susceptibility pattern of the child (or source case’s) isolate and previous TB treatment history. If fixed dose combinations are used, this will be difficult.

On the other hand, in some areas, standardised treatment (all MDR-TB cases get the same treatment) may be used, which may then benefit from an FDC type drug (which has its own problems in practice and development).

Are second-line drugs as effective as first-line drugs in children compared with adults?

The second-line drugs in general are not as effective as the first-line drugs, however, some of the newer second-line drugs are very effective (e.g. the fluoroquinolones). Effectiveness in adults and children should be the same (very difficult to study efficacy in children due to the nature of their disease). Experience tells us that children mostly have good outcomes if diagnosed in timely manner and promptly started on treatment with the correct combination of drugs.

Have drug interactions of several second-line drugs been studied in adults and children?

Interactions between different anti-TB drugs have been studied quite well and the basics of interactions with other drugs are also known, but there is always more to learn and to be studied. New drugs, such as new antiretroviral drugs, are constantly appearing and drug-drug interactions need then to be studied as well.

How well can the adverse effects be studied in children, as they cannot articulate the problems they face after medication?

It is more difficult to assess adverse effects in children compared with adults, but this does not mean it cannot be done or that we should withhold drugs from children who need it to be cured from their disease. We should continuously work at improving our abilities to treat and monitor children as best we can to improve the health of our children, rather that shying away from our responsibilities with the excuse that monitoring adverse effects are difficult.

Full interview online

( The Correspondent is a recipient of the 2013 REACH Lilly MDR-TB Partnership National Media Fellowship for Reporting on TB .)


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