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. An 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.
Prof. Schaaf explained to me by email 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 than adults for most of the first-line drugs, the drugs do not reach the same concentration in their blood when compared with adults getting the same mg/kg body weight dosage. As you suggest, 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, pharmacodynamics, adverse effects and toxicity been well studied and understood for first-line drugs for children, especially infants and those 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), the South African population is mainly fast acetylators (breaking down and eliminating the drug faster) of INH and is different from that of 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 four factors been studied in the case of second-line drugs given to 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 of these drugs in children 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 MDR-TB using 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 to 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 pharmacokinetics 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.
Is there not a high probability of overdosing or underdosing children 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.
Considering that 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 completely 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 at all to come out with 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? Is there any difference between adults and children with respect to effectiveness?
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.
Which component is the most difficult to study — safety, activity, effectiveness, efficacy, dosage, pharmacokinetics or pharmacodynamics? Do children of different age groups react differently to these factors? And is the dosage uniform for children of all age groups for all drugs?
This is very broad question. All of the above can be done (and should be done), either in adults or children. Efficacy studies in children are quite difficult as confirming TB in children is sometimes difficult. Some children will improve even without treatment (although this is not a reason not to treat!). Therefore, huge numbers will need to be studied to show efficacy.
This is why efficacy studies are usually done in adults, and if it works in adults it is most likely going to be effective in children as well. Regarding dosing in children of different ages — as previously explained — they may differ (weight, age, nutritional status, etc), but dosing should be kept as simple as possible for practical purposes.
What is the essential difference between pharmacokinetics and pharmacodynamics?
Pharmacokinetics is what the drug does to the body, while pharmacodynamics is what the body does to the drug – this is the simplest explanation I have read.
Do malnutrition and malabsorption of drugs further complicate serum availability of the drugs in children? Is malnutrition the only factor that causes malabsorption of drugs in children, especially those younger than five years?
Malnutrition and malabsorption are not the same and do not always go together. Malabsorption of drugs may occur for different reasons, e.g, taking drugs with or without food or different kinds of food may play a role. Malnutrition may play a role partially due to malabsorption (also depending on why the child is malnourished) but could also be influenced by body composition and other factors. Studies often differ in their results regarding the effect of malnutrition on specific drugs, such as isoniazid (some say no effect, and others do find an effect).
Most of the anti-TB drugs have been discovered a few decades ago. What is the reason why studies on all aspects of the drugs in children/adults never done much earlier?
I think again there are many reasons — studies were done, but children were often excluded for ethical considerations or volumes of blood needed (nowadays with new methods very small amounts of blood are needed for pharmacokinetic studies).
Is the tiny market size and the fact that TB is a poor man’s disease that prevented pharmaceutical companies from undertaking trials in children? Or is because conducting trials in children is difficult and the true disease burden is not known?
Again, I think there is more than one consideration — relatively small market (and most children still not diagnosed, although this is slowly improving), developing drugs is expensive and companies do not want to invest if there is little chance on monetary return (but this is where we need to challenge them). As explained above, companies are now required to have at least a paediatric development plan if they develop new drugs which could be important for use in children as well.
Considering that WHO declared TB as a global emergency in 1993, why were drugs for children overlooked even by the WHO? Is it because even the WHO only belatedly realised that childhood TB was real and in the developing countries constituted 10-20 per cent of the total TB burden?
Yes, this was definitely part of the problem – the burden of disease in children was overlooked. Children were also not considered to be epidemiologically important (that is, they were not responsible for spreading the disease).
How well can the adverse effects be studied in children, considering the fact that 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 is difficult.
(The Correspondent is a recipient of the 2013 REACH Lilly MDR-TB Partnership National Media Fellowship for Reporting on TB.)