ICAAC: Dividing Triomune tablets may result in inadequate doses for small children; liquid best

Keith Alcorn
Published: 06 January 2006

The study

The study was conducted in nine children receiving treatment at Lilongwe Central Hospital with a median age of 7.2 years and a median weight of 18kg.

All participants initially received Triomune tablets, which combine the three antiretrovirals in one tablet, quartered according to weight (although these tablets are not scored to facilitate division). Tablets were quartered according to the following weight bands and dosed twice daily:

  • 8-<12kg – one-quarter tablet
  • 18-<22kg – one-half tablet
  • 28-32kg – three-quarters of a tablet

All participants had received at least three months of treatment using this dosing schedule before they were randomised either to continue their existing treatment or to switch to either generic or branded liquid formulations.

Drug concentrations were measured six hours after dosing on the tenth day after switching.

In the lowest weight band a clinically significant difference in concentrations of stavudine and lamivudine was noted in children who received the divided generic tablets when compared with those who received liquid formulations – children who received the divided tablets had lower concentrations of these two drugs. Dosing with a divided tablet is not bioequivalent to using liquid formulations, the researchers concluded.

In children with higher body weight there was less difference between plasma concentrations of divided tablets and liquid formulations, but bioequivalence was not proved in all cases.

The study found that generic and branded liquid formulations were bioequivalent, and the US Food and Drug Administration announced last month that it has granted tentative approval to Aurobindo’s stavudine and nevirapine liquid formulations, allowing both to be used by PEPFAR-funded treatment programmes. Both the US FDA and the World Health Organization have approved liquid formulations of lamivudine and of zidovudine produced by generic manufacturers, as well as branded liquid formulations of all these drugs.

The study also found that when compared with historical control data from paediatric patients in the United States, Malawian children had higher plasma concentrations of the branded liquid formulation of nevirapine and substantially lower concentrations of stavudine (1.1ug/ml vs 1.6ug/ml) and lamivudine (3.3 vs 7.1ug/ml).

Multiples of quarter tablets are a reasonable option for larger children, but quarter tablets should not be used children with low body weight, the researchers concluded.

Splitting tablets of fixed dose combinations of d4T (stavudine, Zerit), 3TC (lamivudine, Epivir) and nevirapine (Viramune) in order to contrive doses suitable for small children may result in significant under-dosing of d4T and 3TC, according to results of a pharmacokinetic study conducted in Malawi that was presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington DC last month.

The study compared plasma levels of liquid formulations of nevirapine, stavudine and lamivudine with plasma levels of these drugs in children who received divided tablets, and also compared the bioequivalence of branded and generic formulations of both liquid and tablet products in HIV-positive children.

Paediatric dosing of antiretrovirals is complicated because the rate at which drugs are processed in children changes as they grow, and it is not safe to infer paediatric doses from adult dosing recommendations. So, dividing up tablets may not result in safe or adequate doses of drugs, particularly if several drugs are combined in one tablet.

The use of quartered tablets for dosing of children has been pursued in African countries because of the lack of availability of liquid formulations in some places and for some drugs, the difficulty in storing and reconstituting liquid formulations, the difficulty in calculating doses of liquids based on body weight and surface area, the higher price of liquid formulations and the widespread use of the fixed dose combination product Triomune, which combines nevirapine, stavudine and lamivudine. Medicins Sans Frontieres, for example, has reported that it is far easier to achieve good adherence to quartered tablets in children than it is to ensure that accurate doses of liquid formulation are given consistently.

Reference

Corbett A et al. Pharmacokinetics between trade and generic liquid and split tablet formulations of lamivudine, stavudine and nevirapine in HIV-infected Malawian children. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington DC, abstract H-1106, 2005.