Nevirapine paediatric dosing: adult tablets can be split, Thai study reports

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Dosing of children with fractions of adult fixed dose combination tablets that contain nevirapine (Viramune) can provide the appropriate nevirapine exposure for children of varying ages, a Thai study reports this month in the journal AIDS.

The lack of fixed dose antiretroviral combinations in suitable doses for children of different ages and/or weights has been a major obstacle in providing treatment for children with HIV. Although clinicians have tried to estimate how adult fixed dose tablets can be divided in order to provide appropriate paediatric dosing, there are few data to guide decision-making.

The picture has been further complicated by doubts among some researchers over the applicability of data derived from pharmacokinetic studies in adults, since younger children are known to metabolise drugs differently. In particular it was feared that children might not receive adequate doses of nevirapine, leading quickly to a high level drug resistance, if tablets were halved or quartered. This fear arose because of suggestions that the drug may not be distributed evenly within tablets, and that division of adult tablets could result in uneven dosing.

Glossary

fixed-dose combination (FDC)

Two or more drugs contained in a single dosage form, such as a capsule or tablet. By reducing the number of pills a person must take each day, fixed-dose combination drugs may help improve adherence.

trough level

The lowest point to which levels of a drug fall in the blood between doses.

 

plasma

The fluid portion of the blood.

paediatric

Of or relating to children.

salvage therapy

Any treatment regimen used after a number of earlier regimens have failed. People with HIV who have experienced side-effects and/or developed resistance to many HIV drugs receive salvage therapy, sometimes consisting of a large number of medications.

Thai researchers tested the pharmacokinetic profile of nevirapine contained in GPO-VIR, a fixed dose combination of nevirapine, stavudine (d4T, Zerit) and lamivudine (3TC, Epivir) produced by the Thai Governmental Pharmaceutical Organisation (GPO). This product is the recommended first-line regimen for adults and children in Thailand.

The study enrolled 34 children who had been receiving GPO-VIR at a Bangkok hospital for at least eight weeks (long enough for stable concentrations of nevirapine to have been achieved). The median age was 8.4 years, with the youngest child just three years of age. No child weighed under 9kg. Plasma samples were taken prior to dosing, and two and six hours after dosing. The estimated dose was 120-200mg/m (paediatric dosing is often calculated by body surface rather than body mass).

Dosing

Weight/surface area grouping

No of patients

GPO-VIR dose every 12 h

Calculated daily dosage (mg/m2)

>4 - 9kg (0.23-0.14m2)

0

¼ tablet

244 - 435

>9 - 18kg

(0.46-0.70m2)

11

½ tablet

286 – 434

>18-25

(0.78-0.88m2)

13

¾ tablet

341 – 385

>25-40kg

(0.98-1.2m2)

10

1 tablet

333 - 408

Twenty-four of 34 children received tablets that had been broken up for dosing purposes, and 32 of 34 children were able to swallow the tablets without crushing them.

Results

The target minimum trough level for nevirapine plasma concentrations is 3.4ug/ml. In this study the mean trough level was 6.94ug/ml (median 5.98) and only one child had a trough level below this level.

Four children were taking nevirapine as part of a salvage regimen that also included indinavir (Crixivan) boosted with ritonavir (Norvir). In one of these children the trough concentration of nevirapine was 24.37ug/ml despite the fact that indinavir and ritonavir should not affect nevirapine concentrations.

The study was able to correlate plasma concentrations with virologic response in 13 treatment-naïve children for whom viral load measurements were available. In twelve cases viral load was below 400 copies/ml.

The authors of the study concluded: “It is reassuring that dividing the adult fixed dose combination tablet GPO-VIR does not adversely affect nevirapine bioavailability and can be used to generate paediatric doses between 120 and 200mg/m2.

Limitations of the study

  • The study was not able to describe intracellular levels of stavudine or lamivudine
  • The youngest child was three, so the study is not able to describe the effects of dividing tablets into less than a quarter nor in children at very low weight.
References

Chokephaibulkit K et al. Pharmacokinetics of nevirapine in HIV-infected children receiving an adult fixed-dose combination of stavudine, lamivudine and nevirapine. AIDS 19: 1495-1499, 2005.