HIV Pharmacology Workshop: The dangers of breaking up tablets for paediatric dosing

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Further evidence that dividing adult Triomune tablets for use by children may result in under-dosing was presented last week at the HIV Pharmacology Workshop in Lisbon, and the workshop also heard the first bioequivalence data on a paediatric tablet formulation of Triomune, called Pedimune.

Triomune (a fixed dose combination of stavudine (d4T), lamuvdine (3TC) and nevirapine) is the cheapest regimen available in much of sub-Saharan Africa, and is commonly prescribed to adults. Attempts have been made to estimate doses for children by halving and quartering tablets, but it is unclear if these doses are correct.

A European-African study involving the Radboud University and Nijmegen University in the Netherlands, two African hospitals in Malawi and Zambia respectively and the UK Medical Research Council (MRC) was carried out. The aim of the study was to investigate whether Triomune tablets that are routinely divided for administration, deliver the same active ingredients, particularly in children who are malnourished.

Glossary

pharmacokinetics (PK)

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

plasma

The fluid portion of the blood.

paediatric

Of or relating to children.

body mass index (BMI)

Body mass index, or BMI, is a measure of body size. It combines a person's weight with their height. The BMI gives an idea of whether a person has the correct weight for their height. Below 18.5 is considered underweight; between 18.5 and 25 is normal; between 25 and 30 is overweight; and over 30 is obese. Many BMI calculators can be found on the internet.

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.

Tablets are difficult to split, the drugs are not equally distributed and there are no formal recommendations on how to divide them with the distinct possibility of under-dosing.

A retrospective analysis of 127 HIV-infected children (71 Malawian and 56 Zambian) between the ages of three months and 16 years treated with Triomune in Malawi or Zambia was assessed for steady-state plasma concentrations of nevirapine. 48% of the cohort was female. Height-for-age, BMI-for-age, age, sex, post-dose sampling time and dose/m2/day were stratified for analysis.

The Malawian children were similar ages with a median 8.4 years and were more malnourished (BMI-for-age -0.89, height-for-age -3.15) and had longer post-dose sampling times compared to the Zambian children. The median NVP concentrations were 4.8 (range 2.8-6.5) in Malawian compared to the higher levels in Zambian children at 7.0 (range 5.4-10.5).

The researchers observed that only those receiving doses comparable to the adult dose were in fact receiving the target nevirapine concentration of 300mg/m2/day. 2% were considered to be on sub-therapeutic levels (

Based on these findings, the researchers do not recommend the use of quarter tablets or dividing Triomune in young children to avoid the possibility of nevirapine under-dosing. They also confirm that prescribed below 300mg had a greater likelihood of achieving sub-therapeutic levels. Whilst nevirapine levels may be reduced in children with stunted growth (lower height-for-age), levels were increased in children with wasting syndrome.

An additional pharmacokinetic study by the same Dutch and European authors demonstrated the comparable PK profile of the FDC stavudine, lamivudine and nevirapine (registered names Pedimune Baby and Junior, manufactured by Cipla Pharmaceuticals) against the individual branded agents.

This was a single-centre, open-label one-dose, three-period study (single doses x 3 cycles x 4 weeks each cycle) designed to demonstrate potential differences in bioavailability. Six healthy males with median age, height and body weight range were 43 years (range 21-63), 1.84 metres (range 1.74-1.98), 86.5kg (range 69-1000) respectively, were randomised to receive the following regimens comparing Pedimune Baby, Junior and a reference agents (lamivudine, stavudine or nevirapine):

Regimen 1:

Reference + Pedimune Baby + Pedimune Junior

Regimen 2:

Reference + Pedimune Junior + Pedimune Baby

Regimen 3:

Pedimune Baby + Pedimune Junior + Reference

Regimen 4:

Pedimune Baby + Reference+ Pedimune Junior

Regimen 5:

Pedimune Junior + Reference + Pedimune Baby

Regimen 6:

Pedimune Junior + Pedimune Baby + Reference

Pharmacokinetic curves were recorded at day 1 of every cycle (8 hour PK curve), with additional plasma samples taken at days 2, 3, 4, 8 and 15.

PK parameters of stavudine, lamivudine and nevirapine:

relative bioavailability after intake of single dose of stavudine, Pedimune Baby and Pedimune Junior

 

stavudine

Baby

Junior

Cmax mg/L

     

Geometric mean

0.463

0.463

0.369

Range

0.191-0.544

0.256-0.765

0.294-0.524

AUC mgh/L

     

Geometric mean

1.014

1.224

1.041

Range

0.729-1.540

0.846-1.715

0.672-1.507

 

lamivudine

Baby

Junior

Cmax mg/L

   

Geometric mean

1.127

1.264

1.026

Range

0.550-1.562

0.700-1.917

0.829-1.241

AUC mgh/L

     

Geometric mean

4.412

5.007

4.368

Range

3.480-5.591

3.570-6.499

3.660-5.754

 

nevirapine

Baby

Junior

Cmax mg/L

     

Geometric mean

1.94

1.62

1.89

Range

1.64-2.29

0.96-2.91

1.48-2.48

AUC mgh/L

     

Geometric mean

129.88

122.86

118.50

Range

85.04-203.58

88.15-199.39

77.38-246.8

The study established comparable pharmacokinetic profiles between branded compounds, Pedimune Baby and Pedimune Junior. A formal bioequivalence study by Cipla has not yet been completed, but these data anticipate positive results. With the urgent need for paediatric treatment in the developing world and the dearth of available treatments appropriate for children, these study results are both important and welcome.

References

L’homme R et al. Nevirapine concentrations in HIV-infected children treated with divided fixed dose combination tablets in Malawi and Zambia. HIV Pharmacology Workshop, Lisbon, abstract 2, 2006.

L’homme R et al. Pharmacokinetics of two generic fixed dose combinations for HIV-infected children (Pedimune Baby and Pedimune Junior) are comparable to the branded products. HIV Pharmacology Workshop, Lisbon, abstract 23, 2006.