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HIV Pharmacology Workshop: The dangers of breaking up tablets for paediatric dosing
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.
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 (<3mg/l), whilst those prescribed quarter to half tablets (50-200 mg/day were more likely to be under-dosed, as were those prescribed more than 200 but less than 350mg. Lower prescribed dose, lower height-for-age and younger age were all independently associated with lower levels of nevirapine. BMI-for-age was a stronger predictor in Malawian children, indicating higher levels of wasting.
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):
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
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.
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.
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 (<3mg/l), whilst those prescribed quarter to half tablets (50-200 mg/day were more likely to be under-dosed, as were those prescribed more than 200 but less than 350mg. Lower prescribed dose, lower height-for-age and younger age were all independently associated with lower levels of nevirapine. BMI-for-age was a stronger predictor in Malawian children, indicating higher levels of wasting.
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 mg•h/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 mg•h/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 mg•h/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.
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