Recognised as a world leader and a prominent clinical researcher in South Africa

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1 Expert Talks Prof. Peter Donald Emeritus professor in Pediatrics and Child Health at the Faculty of Health Sciences of the University of Stellenbosch and Tygerberg Children's Hospital, South frica n internationally known researcher leading the quest to cure tuberculosis Renowned for his ground breaking basic and clinical research on tuberculosis 30 years experience tuberculosis research in the terrain of Recognised as a world leader and a prominent clinical researcher in South frica He specialises in different aspects of tuberculosis, including epidemiology, Pediatrics and TB meningitis. He is on the forefront regarding research on childhood tuberculosis and the combined TB-HIV epidemics in South frica. His cutting edge research and skills has laid the foundation for the clinical evaluation of the first new antituberculosis drugs to be developed in 40 years. Without this initial groundwork in developing the technique of determining the early bactericidal activity of antituberculosis drugs in conjunction with pharmacokinetic studies, the evaluation of these new agents could not have been undertaken so expeditiously. Prof. Donald has received many honours for his extraordinary commitment. He was awarded the Union Medal, of the International Union against Tuberculosis and Lung Disease, at the 2010 General ssembly in Berlin, Germany. The Union awards this medal to people who made outstanding contributions to tuberculosis and non-tuberculosis lung disease. He was also recognized for his contributions to child lung health and especially childhood tuberculosis. 37

2 Childhood TB Management - Opening New Doors of Hope How can we assess global demand of anti-tb drugs required to treat TB in children if we do not have a sense of the disease burden? This is a very pertinent question and brings into focus the economic viability of any attempt to develop child friendly formulations of antituberculosis agents. Estimates of the number of children suffering from tuberculosis have been attempted and we know that children constitute approximately 5% of number of individuals being treated for tuberculosis in developed countries, but that, in deprived communities within developing countries, the proportion of children can rise to as high as 40% of the tuberculosis burden, although it will usually be closer to 20%. World-wide children may constitute approximately 10% of the estimated tuberculosis burden. ny interpretation of numbers is complicated by the fact that it was practice, until recently, to report only those cases of childhood tuberculosis that were sputum smear microscopy-positive. s the majority of childhood tuberculosis is smear-negative this would clearly lead to an under-estimate. In 1989 a report of the Expanded Programme of Immunization of World Health Organization reported 1.3 million cases of tuberculosis in children and the death of 450,000 as result of tuberculosis. (World Health Organization. 1989) later report for 1990 estimated the number of children with tuberculosis world-wide at 650,000. (Kochi 1991)The accelerating impact of HIV-infection and its associated influence on tuberculosis will also now be much more serious; making use of statistical techniques to model the tuberculosis epidemic it was suggested in 2003 that the the number of childhood (age < 15 years) cases of tuberculosis was approximately 884,000 or 10.7% of the total burden world-wide. (Corbett et al. 2003) In considering the global burden of childhood tuberculosis from the perspective of the number of children requiring paediatric formulations a further consideration is that from approximately 10 years of age children can be treated with adult formulations and, without too much loss of accuracy, with adult mg/kg body weight doses of antituberculosis drugs. Clearly this is an area where more accurate data is needed. Perhaps the old auditing practice of sampling should be put into practice to more accurately estimate the number of childhood cases of tuberculosis in a selected number of clinics stratified for socio-econimic status, in countries throughout the world. n alternative strategy would be to request the reporting of all children treated for tuberculosis with two or more drugs, regardless of smear status. (Nelson LJ, Wells CD 2004) 38 01

3 Is there truly a need for child friendly medications? Without any doubt appropriate formulations are desperately needed for children. One need only go the extremes of age to appreciate this more easily. For children less that 10 kg the situation often exists, particularly in peripheral clinics, that only adult tablets are available. In a large teaching hospital there may be pharmacists available who can make a reasonably accurate suspension of an agent, but in peripheral communities this is not feasible This leads to a situation where, attempting to arrive at a suitable dose of a drug for a young child, the clinic staff may take a kitchen knife to halve an adult tablet and then, perhaps, will have to halve it again. This must lead to inaccuracies and the possibility of under dosing affecting efficacy and over-dosing that could precipitate toxicity. In the early twenty first century this is no longer an acceptable situation. What are the major bottlenecks to delivery of care to children with TB? The first bottleneck, and some would argue the most important, is the failure to diagnose tuberculosis in a child or even consider the diagnosis, despite the presence of tuberculosis in a household. Similarly the diagnosis of tuberculosis in any adult should automatically lead to the question: Does this patient have any contact with children, especially young children or immune-compromised children? This creates the possibility of not only diagnosing tuberculosis in a child before major complications such as meningitis have occurred, but also creates an opportunity for chemoprophylaxis; the fact that another household member must in any event receive tuberculosis therapy makes it far more likely the child will receive treatment or chemoprophylaxis, as appropriate. The difficulty of diagnosing tuberculosis in children is often considered an obstacle; while this is acknowledged, the major difficulty is that the diagnosis is not even considered in the first place. Once the diagnosis has been considered, history, a Mantoux or other tuberculin skin test or serological test and, if available, a chest radiograph, may help the diagnosis. Even when a chest radiograph is available there may be difficulty in interpreting it and this is particularly likely with an inexperienced reader and a poor quality radiograph. gain the important step in this situation is to re-examine the child and reconsider the history. Even in the absence of special investigations, such as chest radiography, symptomatic 39 01

4 children, with or without clinical signs, known to have been in close contact with a sputum microscopy smearpositive adult, should be placed on antituberculosis therapy. This is particularly important in the very young where the risk of disseminated forms of tuberculosis, suchastuberculousmeningitisormiliarytuberculosis,is veryhigh. Other diagnoses must of course be considered, but it is the delay in starting tuberculosis therapy timeously when the index of suspicion should be high that does the most damage. s with new drugs there are exciting developments taking place in the field of diagnosing childhood tuberculosis, but even with new technologies available the diagnosis must first be considered! Having diagnosed tuberculosis the availability of appropriate formulations becomes an important issue, particularly in younger children and a majority of children in the world are probably managed with ad hoc preparations of adult formulations. Do children need higher mg/kg doses of drugs? The answer to this question is an ambiguous, yes and no! This highlights the most important issue that in many instances we lack the data to make a definitive answer to this question and it may vary from drug to drug depending upon the pharmacokinetics of the drug in question. There is thus little doubt that children require higher mg/kg body weight doses of isoniazid, (Donald et al. 2011) rifampicin (Donald et al. 2011) and ethambutol (Donald et al. 2006) to reach serum concentrations equivalent to those following an efficacious dose of the drug in adults. In the case of pyrazinamide there remains some uncertainty, (Donald et al. 2012) but it is likely that children receiving the same mg/kg dose as adults will achieve the same exposure to the drug as adults. Thus while it remains a reasonable guess that children will usually require a higher mg/kg dose of any drug than adults, we cannot know this with certainty until we have the data; the answer may be different, not only for different drugs, but may differ for the same drug at different ages

5 How can it be that optimal paediatric dosing was only assessed yrs after initial drug discovery/clinical use? I think we must see this from an historical perspective. t the time of the discovery of antituberculosis drugs, and for some years afterwards, the major perceived need was to reach as many adult patients as possible. There was great relief that at last chemotherapy for tuberculosis was available, irrespective if it was children or adults that were being treated. There was also a need to simplify regimens so that they could easily be made available to the enormous numbers of patients that had to be treated in both developed and developing countries. Once tuberculosis rates began to decline in developed countries scientific interest (and financial interest) declined and it appeared to be felt that as tuberculosis rates were declining all over the world, albeit slowly in some countries, if we were patient and diligently applied the recommended programmes, the problem would eventually disappear. This approach had to be finally abandoned in the face ofthe HIVepidemic. During this whole period children were perceived as being a minor part of the problem and it appeared that they responded satisfactorily to the doses of antituberculosis drugs recommended. Examining the early literature describing the treatment of childhood tuberculosis it is also clear that many paediatricians were actually using higher doses of antituberculosis drugs than were later recommended by many official bodies such as World Health Organization. The second problem is the very nature of childhood tuberculosis. Tuberculosis in children can range from mild enlargement of hilar nodes to overt cavitation with all the features of adult disease or miliary disease with usually fatal consequences. On the one hand the milder forms of childhood tuberculosis may regress without treatment and can probably be satisfactorily treated in many cases with low doses of the relevant drugs; on the other hand life-threatening tuberculosis disease in children requires the same exposure to efficacious doses of multidrug therapy as adult disease. Many experienced practitioners will point out that they have been treating childhood tuberculosis for many years at the lower, previously recommended doses, without any noticeably poorer results. Why then increase the doses? gain I think the answer lies in the nature of the disease that is being treated. In adult studies we now know that there is for most antituberculosis drugs a dose-related response. Lower the dose in adults and, particularly in severe disease, the response will be less satisfactory. The same applies to childhood disease; at lower doses there may still be a response, but particularly in severe disease this response may not be as rapid, nor as satisfactory, as that following more appropriate higher doses of drugs

6 How can we prevent this from happening again in the future? The response to this problem lies with the regulatory agencies. The financial incentive for any pharmaceutical company to study the pharmacokinetics of any drug in children will often be limited. It is now required by the FD and EM that companies should present a plan for the investigation of the pharmacokinetics of any new drug in children; this will also entail the preparation of appropriate formulations. The evaluation of the efficacy of an antituberculosis drug in children is probably not necessary, but the determination of the dose range that will lead to the exposure of children of different ages to the same concentrations as adults receiving an efficacious dose of the drug is essential. It is thus certain that we will soon have data to delineate the appropriate doses for children of the new antituberculosis drugs now in clinical development. Did the new dosage recommendation have a positive or negative impact on drug availability/care delivery? I think it is too early to comment upon this; however one positive development is the considerable amount of debate regarding doses and the pharmacokinetics of antituberculosis drugs in children that has arisen. This can only have a beneficial effect in the long run, focussing attention on the need to see children as a group of tuberculosis patients with their own needs and requirements and providing the stimulus for further studies of our existing drugs in children of all ages

7 Seeing that there are no ideal formulations on the market at present, what is the best pragmatic interim solution? For all pharmacological interventions there will usually be a range of doses over which a similar therapeutic response may be expected. Precise accuracy is thus not necessary for most antituberculosis agents. With available agents one can come fairly close to the newly recommended dose ranges by manipulating existing formulations. Using the available adult formulations of fixed-dose combinations of two or three or four drugs it is also often possible, to come fairly close to what one wants, for example by using only one tablet of a fixed dose formulation for young children. If single drug preparations are available these can also be used to supplement other formulations to achieve the required dosage. To circumvent confusion following the publication of the newly recommended doses for antituberculosis drugs in children WHO released a interim document in 2009 to assist in utilising existing paediatric formulations. These guidelines can be accessed on the following links: tric%20fdcs%20dosing%20instructions%20for%20prescribers_sept09.pdf tric%20fdcs%20detailed%20dosing%20instructions_sept09.pdf manipulating existing formulations designed for adults or, if available, for children. The further problem is administering the tablets to a very young child and it will probably be necessary to crush the tablets immediately before they are given and to administer the crushed tablets with a food familiar, or acceptable, to the child. The remnant of a crushed or cut tablet should then be discarded and not used as rapid deterioration may occur. This sort of practice is not ideal, but may be necessary as an interim measure to reach the newly recommended doses for children. Suggested reading 1. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. rch Intern Med. 2003;163: Donald PR, Maher D, Maritz JS, azi S. Ethambutol dosage for the treatment of children: literature review and recommendatiions. Int J Tuberc Lung Dis. 2006;10: Donald PR, Schaaf HS. Isoniazid pharmacokinetics and efficacy in adults and children. Progr Resp Research. 2011;40: Donald PR, Maritz JS, Diacon H. The pharmacokinetics and pharmacodynamics of rifampicin in adults and children in relation to the dosage recommended for children. Tuberculosis. 2011;91: Donald PR, Maritz JS, Diacon H. Pyrazinamide pharmacokinetics and efficacy in adults and children. Tuberculosis. 2012:92; Kochi. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle. 1991;72: Nelson IJ, Wells CD. Global epidemiology of childhood tuberculosis. Int J Tuberc Lung Dis. 2004;8: WorldHealthOrganization.Expandedprogramonimmunization,update,ugust1989,Geneva. In the absence of formulations designed specifically for children one must make use of what is available and can come fairly close to the newly recommended dose ranges by 43 01