Children may benefit from a higher dose of nevirapine than recommended by manufacturer

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HIV-positive children show better virological and immunological outcomes when treated with doses of nevirapine (Viramune) higher than those recommended by its manufacturer, Boehringer Ingelheim, according to a retrospective analysis of pharmacokinetic data presented this week at the Seventh International Congress on Drug Therapy in HIV Infection in Glasgow.

Current dosing guidelines for nevirapine in children recommend 120mg/m2 per day for children aged under eight. In children aged eight years or older, an initial dose of 120mg/m2 per day is recommended for the first two weeks, before increasing to 150mg/m2 per day. However, these guidelines are based on the findings of two small studies including a total of 46 patients. The retrospective study, presented by medical student Anet Alexanian from Imperial College, London, was carried out to compare drug doses with blood concentrations of nevirapine and clinical outcomes.

The investigators obtained the results of 111 nevirapine measurements from 51 children aged between 2 months and 15 years from a database held at the Liverpool Therapeutic Drug Monitoring Service. Nevirapine levels had been measured at four hours after dosing, so estimated trough concentrations were calculated using the half-life determined from adult pharmacokinetic studies.

Glossary

retrospective study

A type of longitudinal study in which information is collected on what has previously happened to people - for example, by reviewing their medical notes or by interviewing them about past events. 

trend

In everyday language, a general movement upwards or downwards (e.g. every year there are more HIV infections). When discussing statistics, a trend often describes an apparent difference between results that is not statistically significant. 

white blood cell

The cells of the immune system, including basophils, lymphocytes, neutrophils, macrophages and monocytes. Also known as a leukocyte.

 

toxicity

Side-effects.

plasma

The fluid portion of the blood.

Trough levels of nevirapine were found to be greater in patients receiving higher doses of the drug (p

Higher drug trough concentrations were associated with lower viral loads (p = 0.012) and higher CD4 cell counts, expressed as age-corrected z-scores (p = 0.002). Furthermore, the children who had undetectable viral loads had higher trough concentrations of nevirapine than those who never achieved undetectability (p = 0.026).

There was also a non-significant trend for patients taking nevirapine once daily to have lower trough nevirapine concentrations than those taking it twice daily, as recommended (p = 0.064).

The investigators found evidence of elevated liver enzymes in seven children, although the chances of this occurring were unrelated to trough nevirapine concentrations. This suggests that the higher doses of nevirapine received by some patients did not cause an increased incidence of liver toxicity. There were no reported cases of grade 3 or 4 rash or granulocytopenia, low levels of granulocytes, a type of white blood cell.

“Higher doses of nevirapine are associated with higher plasma trough concentrations which correlate with better virological and immunological outcomes with no dose-related hepatotoxicity,” conclude the investigators. “The data support the use of nevirapine doses greater than those currently recommended by the manufacturers.”

Despite these findings, the investigators fell short of recommending a revised dose for use in children. More research will be required to pin down the appropriate dose of nevirapine, for children both in industrialised and developing countries. Pharmacokinetic studies to determine the appropriate dose of nevirapine for use in undernourished children who are underweight for their age by Western standards are particularly needed, along with investigations into the different tablet sizes that should be made available for older children and how doses should be adjusted for body weight when children are underweight for their age.

References

Alexanian A et al. Higher nevirapine doses correlate with improved outcomes in a paediatric population. Seventh International Congress on Drug Therapy in HIV Infection, Glasgow, abstract PL11.2, 2004.