The World Health Organization has issued a call for more pharmaceutical companies to develop d4T and AZT-based fixed dose antiretroviral combinations suitable for use in children of varying ages as part of the drive to expand treatment opportunities for children with HIV in developing countries.
The range of antiretroviral drugs suitable for children is limited in comparison with those for adults, partly because not all antiretroviral drugs are available in paediatric formulations. However WHO and other organisations advocating for better treatment for children with HIV say that the priority must be the development of medicines which are easier to take.
Most paediatric formulations produced by innovator and generic manufacturers have come in forms that need to be reconstituted as liquids from powder, or else require the storage of liquids. Liquids are difficult to measure accurately, especially when three drugs must be combined.
Solid tablets which contain doses suitable for children do not exist, and fixed dose combinations like those now available for adults are still being explored. Three companies, Cipla, Emcure and Ranbaxy, are currently testing combinations of d4T, 3TC and nevirapine that each contains slightly different ratios of each drug, reflecting the disagreements that still exist about the appropriate doses of each drug for children of different ages and weights.
There is also confusion in the field over when it is appropriate to divide adult tablets into halves or quarters, and at what age and weight band dosing of children with adult fixed dose combination tablets can begin.
An expert panel convened by WHO in 2006 has now identified a range of products that it would like to see developed in order to make treatment for children easier. They are asking manufacturers to consider the following steps:
- Adhering to a common standard for the ratios of each drug within a fixed drug combination. For example, any AZT/3TC/nevirapine fixed dose tablet would contain 60mg of AZT. 30mg of 3TC and 55mg of nevirapine, and a d4T/3TC/nevirapine tablet could contain 7mg of d4T, 30mg of 3TC and 55mg of nevirapine.
- Adhering to a common standard for dosing of each tablet, according to a child’s weight. For example, children weighing between seven and 11.9kgs would receive one and a half tablets of any drug. Thus, changes in the number of tablets needed for any fixed dose combination would always occur at the same weight, even if children were switched between drugs or different children in the same clinic were receiving different drugs.
- Scoring all tablets to make them easier to cut in half.
- Treat as urgent the need for development of fixed dose AZT/3TC and d4T/3TC tablets for children, in addition to heat stable, scored tablets lopinavir/ritonavir tablets at a dose of 90mg of lopinavir and 22.5mg of ritonavir. Scored abacavir and nevirapine tablets are also highlighted as urgent.
The WHO panel is also calling on international regulatory authorities, which have been slow to embrace the idea of fixed dose tablets for children, to take immediate steps to expedite the approval of standardised products which use different ratios of antiretroviral drugs from those found in adult fixed dose combination tablets, without the need for extensive new bioequivalence studies.
Further details of the WHO recommendations can be found at http://www.who.int/hiv/mediacentre/news63/en/index.html