Splitting Triomune tablets for children: smallest get poorest nevirapine dose

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More evidence that splitting adult antiretroviral tablets for children results in sub-optimal dosing was presented last week at the Sixteenth International Conference in Toronto, with a study from Zambia and Malawi showing that splitting Triomune tablets may lead to serious under-dosing of nevirapine, especially in smaller children under 30kg who received quartered tablets.

Difficulties in dosing liquid formulations of antiretrovirals, coupled with their high cost, have led to the widespread practice of splitting adult antiretroviral tablets in order to dose HIV-positive children with a more convenient form of medication.

Most commonly, adult tablets of the triple combination tablet Triomune (containing d4T, 3TC and nevirapine) are halved or quartered for children, with the Triomune 30 tablet (which contains 30mg of d4T for patients weighing less than 60kg) used in some cases in order to approximate correct paediatric doses.



Of or relating to children.


The physical form in which a drug is manufactured or administered. Examples of formulations include tablets, capsules, powders, and oral and injectable solutions. A drug may be available in multiple formulations.

concentration (of a drug)

The level of a drug in the blood or other body fluid or tissue.

pharmacokinetics (PK)

How drugs are processed and used in the body, including how they are absorbed, metabolised, distributed and eliminated.


The fluid portion of the blood.

However, deriving paediatric doses from adult tablets is difficult due to limited information about the correct doses needed at different weights and heights, and by the fact that paediatric dosing is calculated by body surface area rather than by weight or age. A further and poorly understood complication in this population is how malnutrition might affect the pharmacokinetics of antiretroviral drugs.

Under-dosing of nevirapine could result in the rapid emergence of resistance to the drug, particularly if the paediatric dose is not updated to reflect changes over time in the child's weight in the youngest children.

Researchers from Zambia, Malawi, the United Kingdom’s Medical Research Council and the University of Nijmegen in the Netherlands conducted a large pharmacokinetic study in 127 HIV-positive children aged from eight months to 18 years of age, recruited from two hospitals in Lusaka (Zambia) and Blantyre (Malawi).

Children received Triomune tablets that had been halved or quartered for one month before single plasma samples were collected from each child. Malawian samples tended to be taken at a longer interval after dosing (eight hours vs three hours), and the 71 Malawian children were more malnourished.

The researchers found that the target nevirapine dose (>300mg/m2 was not reached in just over half of the children, with children weighing less than 30kg significantly more likely to have sub-optimal concentrations.

The median nevirapine concentration was 6mg/L, but 21% of those receiving quarter or half tablets had concentrations below 3mg/L, a sub-therapeutic drug concentration.

Thirty-five per cent of children under the age of three had sub-therapeutic drug concentrations, compared to 25% of 7-10 year-olds and 9% of those aged 11 and over.

Wasted children had higher nevirapine concentrations than children of average body weight (body weight was reported as body mass index for age), but stunted children had lower than average nevirapine concentrations, indicating the need for further study of the effects of malnutrition on nevirapine pharmacokinetics in children, said Veronica Mulenga of the University Teaching Hospital in Lusaka, presenting the results.

The clinic is now carrying out a paediatric pharmacokinetic study of Cipla’s fixed dose triple combination for children, called Pedimune. This product has been formulated with the aim of providing more accurate doses of d4T, 3TC and nevirapine for children, and will be the first study in children of the bioequivalence of a tablet formulation of a fixed dose antiretroviral product with the liquid formulation.


Mulenga V et al. Nevirapine concentrations in HIV-infected children treated with divided fixed dose combination tablets in Malawi and Zambia. Sixteenth International AIDS Conference, Toronto, abstract WeAb0305, 2006.