“The ultimate goal of evidence-based drug treatment is to produce a desired pharmacological response in a predictable manner and also to minimise adverse effects,” notes a June 2013 paper published in the International Journal of Tuberculosis and Lung Disease. The two goals can be achieved only when the correct therapeutic drug dosage of anti-TB drugs required by children, particularly those younger than five years, and the age-related differences in toxicity and pharmacokinetics are well studied and known.
“Pharmacokinetics is the metabolism of the drugs in humans,” Dr. Peter R. Donald, Emeritus Professor in the Department of Paediatrics and Child Health of the Faculty of Health Sciences at Stellenbosch University, South Africa said in an email to this Correspondent. “The pharmacokinetics of first-line anti-TB drugs is not known for children younger than two years.”
Since children have “relatively greater mass of liver in proportion to total body weight,” they metabolise and eliminate drugs faster than adults. As a result, higher mg/kg body weight dosages are needed by them to achieve equivalent concentration of drug in the blood.
In 2010, the World Health Organisation (WHO) revised the first-line anti-TB drug dosage after several studies pointed out that children treated with the same dosage as given to adults achieved only sub-therapeutic effects. The 2010 revision by WHO was possible as the pharmacokinetics of the first-line TB drugs were generally known.
But despite following the WHO’s revised dosages for three first-line anti-TB drugs — isoniazid, rifampicin, and pyrazinamide — children younger than three years in India were found to have “significantly lower rifampicin, isoniazid and pyrazinamide [serum] concentrations than older children. And 90 per cent of all children [across all age groups] had sub-therapeutic rifampicin peak concentration,” notes a June 2013 study by Dr. Geetha Ramachandran and others.
Dr. Ramachandran is from the Chennai-based National Institute for Research in Tuberculosis (NIRT), and the results were published in the International Journal of Tuberculosis and Lung Disease.
The first of its kind study undertaken in India found that pharmacokinetics was affected in children who were younger than three years, stunted and weighed less for their age, and belonged to the rapid isoniazid acetylator group — who had more of the enzyme that converted the isoniazid drug into another compound (acetyl isoniazid) which is devoid of anti-TB properties.
“The concentration of the enzyme is genetically determined,” said Dr. Ramachandran. “Indians are predominantly slow acetylators. About 60 per cent belonged to the slow acetylator group and 40 per cent to the rapid acetylator group.” Slow acetylators tend to have higher isoniazid serum levels.
The study found that children who were malnourished had lower drug levels. “Absorption is likely to be impaired in a malnourished child leading to low drug levels in blood,” she said. “Low drug levels could be due to various factors. So we cannot pinpoint one.”
Besides the lower drug levels in this category of children, RNTCP has four fixed weight bands — 6-10 kg, 11-17 kg, 18-25 kg and 26-30 kg. Aside from the overall underdosing in stunted and underweight children who were rapid acetylators, the drug levels would get further affected in those falling in either extreme of a particular weight band.
“Sustained sub-optimal drug levels could predispose to development of drug resistance and poor treatment outcomes,” the paper notes. But a 2011 paper in the Antimicrobial Agents and Chemotherapy journal states: “higher doses might not be required in paediatric populations with predominantly slow acetylators and would unnecessarily expose patients to a higher risk of side effects.”
Indian population has nearly 60 per cent of slow acetylators. “Slow acetylators are restricted to only isoniazid and does not include other drugs,” she pointed out.
An April 2009 paper in the BMC Medicine journal also found that while nutritional status of children who were HIV-negative improved significantly after four months of treatment, the rifampicin plasma “remained low, so that poor nutrition cannot fully explain this finding.”
(The Correspondent is a recipient of the 2013 REACH Lilly MDR-TB Partnership National Media Fellowship for Reporting on TB.)